Azole derivatives

ABSTRACT

The present invention relates to a compound of the formula (I): 
                         
wherein Az is a group comprising a monocyclic azole or a bicyclic aromatic ring of the same or different fused azoles; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent, and at least two of T, U, V and W are said methine groups; and X is nitrogen or methine.
 
     The compounds of the present invention are useful as agents for the treatment of various kinds of diseases related to NPY, for example, cardiovascular disorders, nervous system disorders, genitative diseases, metabolic diseases, genital or reproductive disorders, gastrointestinal disorders, respiratory disorders, inflammatory diseases or glaucoma, and the like.

This application is a U.S. national stage of International ApplicationNo. PCT/JP2003/015018 filed Nov. 25, 2003.

TECHNICAL FIELD

The present invention is useful in medical fields. In more detail, novelazole derivatives of the present invention have an effect asneuropeptide Y receptor antagonists and are useful as agents for thetreatment of various kinds of cardiovascular disorders, nervous systemdisorders, metabolic diseases, genitalor reproductive disorders,gastro-intestinal disorders, respiratory disorders, inflammatorydiseases or glaucoma, and the like.

BACKGROUND ART

Neuropeptide Y (hereinafter referred to as NPY), a peptide consisting of36 amino acids, was first isolated from porcine brain by Tatemoto et alin 1982 (NATURE, vol. 296, p. 659 (1982)). NPY is widely distributed incentral nervous system and peripheral nervous system, and plays variousroles as one of the most abundant peptides in the nervous system. Thatis, NPY acts as an orexigenic substance in the central nervous systemand markedly promotes fat accumulation via the mediation of secretion ofvarious hormones or the action of the nervous system. It is known thatcontinuous intracerebroventricular administration of NPY induces obesityand insulin resistance due to these actions (INTERNATIONAL JOURNAL OFOBESITY, vol. 19, p. 517 (1995);Endocrinology, vol. 133, p. 1753(1993)). It is also known that NPY has central actions such asdepression, anxiety, schizophrenia, pain, dementia, circadian rhythmcontrol and the like (DRUGS, vol. 52, p. 371 (1996); THE JOURNAL OFNEUROSCIENCE, vol. 18, p. 3014 (1998)). Furthermore, in the periphery,NPY coexists with norepinephrine in sympathetic-nerve terminals and isrelated to the tonicity of the sympathetic nervous system. It is knownthat peripheral administration of NPY causes vasoconstriction andenhances the activities of other vasoconstrictive substances such asnorepinephrine (BRITISH JOURNAL OF PHARMACOLOGY, vol. 95, p. 419(1988)). It is also reported that NPY could participate in thedevelopment of cardiac hypertrophy as a result of the sympatheticstimulation (PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THEUNITED STATES OF AMERICA, vol. 97, p. 1595 (2000)).

On the other hand, it is reported that NPY is also involved in thesecretory function of sexual hormones and growth hormone, sexualbehavior and reproductive function, gastro-intestinal motility,bronchoconstriction, inflammation and alcohol preference (LIFE SCIENCE,vol. 55, p. 551 (1994); THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY,vol. 101, p. S345 (1998); NATURE, vol. 396, p. 366 (1998)).

NPY has a variety of pharmacological effects resulting from NPY bindingto some NPY receptors to which peptide YY and pancreatic polypeptide,which are the analogs of NPY, also bind. It is known that thesepharmacological effects of NPY are mediated by the action of at leastfive receptors with or without synergistic interactions (TRENDS INNEUROSCIENCES, vol. 20, p. 294 (1997)).

It is reported that the central effects mediated by NPY Y1 receptorinclude remarkable orexigenic effect (ENDOCRINOLOGY, vol. 137, p. 3177(1996); ENDOCRINOLOGY, vol. 141, p. 1011 (2000)). Further, NPY Y1receptor is reported to be involved in anxiety and pain (NATURE, vol.259, p. 528 (1993);BRAINRESEARCH, vol. 859, p. 361 (2000). In addition,the pressor effect mediated by the strong vasoconstrictor action in theperiphery is also reported (FEBS LETTERS, vol. 362, p. 192 (1995);NATURE MEDICINE, vol. 4, p. 722 (1998)).

It is known that the effects mediated by NPY Y2 receptor include aninhibitory effect on the release of various neurotransmitters in thesympathetic nerve endings (BRITISH JOURNAL OF PHARMACOLOGY, vol. 102, p.41 (1991); SYNAPSE, vol. 2, p. 299 (1988)). In periphery, NPY Y2 causesconstriction of blood vessel or vas deferens directly or via the controlof release of various neurotransmitters (THE JOURNAL OF PHARMACOLOGY ANDEXPERIMENTAL THERAPEUTICS, vol. 261, p. 863 (1992); BRITISH JOURNAL OFPHARMACOLOGY, vol. 100, p. 190 (1990)). Inhibition of lipolysis inadipose tissues is also known (ENDOCRINOLOGY, vol. 131, p. 1970 (1992)).Further, inhibition of ion secretion in the gastro-intestinal tract isreported (BRITISH JOURNAL OF PHARMACOLOGY, vol. 101, p. 247 (1990)). Onthe other hand, the effects on the central nervous system functions suchas memory, anxiety and the like are also known (BRAIN RESEARCH, vol.503, p. 73 (1989); PEPTIDES, vol. 19, p. 359 (1998)).

It is reported that NPY Y3 receptor exists mainly in brainstem andheart, and is related to the regulation of blood pressure and heart rate(THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 258, p.633 (1991); PEPTIDES, vol. 11, p. 545 (1990)). It is also known thatNPYY3 is involved in the control of catecholamine secretion in adrenalgland (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol.244, p. 468 (1988); LIFE SCIENCE, vol. 50, p. PL7 (1992)).

NPY Y4 receptor has high affinity for pancreatic polypeptide inparticular. As for the pharmacological effects of NPY Y4, inhibition ofpancreatic exocrine secretion and gastro-intestinal motility is reported(GASTROENTEROLOGY, vol. 85, p. 1411 (1983)). Further, it is reportedthat NPY enhances the secretion of sexual hormones in the centralnervous system (ENDOCRINOLOGY, vol. 140, p. 5171 (1999)).

As for the effects mediated by NPY Y5 receptor, fat accumulation effectsincluding orexigenic effect are prominent (NATURE, vol. 382, p. 168(1996); AMERICAN JOURNAL OF PHYSIOLOGY, vol. 277, p. R1428 (1999)). Itis also reported that the NPY Y5 receptor mediates some CNS effects,such as seizure and epilepsy, or pain and morphine withdrawal symptoms,and the control of circadian rhythm (NATURE MEDICINE, vol. 3, p. 761(1997); PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITEDSTATES OF AMERICA, vol. 96, p. 13518 (1999); THE JOURNAL OF PHARMACOLOGYAND EXPERIMENTAL THERAPEUTICS, vol. 284, p. 633 (1998);THE JOURNAL OFNEUROSCIENCE, vol. 21, p. 5367 (2001). In addition, diuretic effect andhypoglicemic effect in the periphery are reported (BRITISH JOURNAL OFPHARMACOLOGY, vol. 120, p. 1335 (1998);ENDOCRINOLOGY, vol. 139, p. 3018(1998)). NPY is also reported to enhance cardiac hypertrophy as a resultof the sympathetic accentuation (PROCEEDINGS OF THE NATIONAL ACADEMY OFSCIENCES OF THE UNITED STATES OF AMERICA, vol. 97, p. 1595 (2000)).

The effects of NPY are expressed when NPY binds to the NPY receptors inthe central or peripheral nervous system. Therefore, the action of NPYcan be prevented by blocking its binding to NPY receptors. For thisreason, it is expected that substances antagonize NPY binding to NPYreceptors may be useful for the prophylaxis or treatment of variousdiseases related to NPY, for example cardiovascular disorders such asangina, acute or congestive heart failure, myocardial infarction,hypertension, nephropathy, electrolyte abnormality, vasospasm, etc.,central nervous system disorders such as bulimia, depression, anxiety,seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal,circadian rhythm disorders, schizophrenia, memory impairment, sleepdisorders, cognitive impairment, etc., metabolic diseases such asobesity, diabetes, hormone abnormality, gout, fatty liver, etc., genitalor reproductive disorders such as infertility, preterm labor, sexualdysfunction, etc., gastro-intestinal disorders, respiratory disorders,inflammatory diseases or glaucoma, and the like. (TRENDS INPHARMACOLOGICAL SCIENCES, vol. 15, p. 153 (1994); LIFE SCIENCE, vol. 55,p. 551 (1994); DRUGS, vol. 52, p. 371 (1996); THE JOURNAL OF ALLERGY ANDCLINICAL IMMUNOLOGY, vol. 101, p. S345 (1998); NATURE, vol. 396, p. 366(1998); THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol.284, p. 633 (1998); TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 20, p. 104(1999); PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITEDSTATES OF AMERICA, vol. 97, p. 1595 (2000); THE JOURNAL OF NEUROSCIENCE,vol. 21, p. 5367 (2001); PHARMACOLOGY & THERAPEUTICS, vol. 65, p. 397(1995); ENDOCRINOLOGY, vol. 140, p. 4046 (1999); AMERICAN JOUNARL OFPHYSIOLOGY, vol. 280, p. R1061 (2001); AMERICAN JOUNARL OF PHYSIOLOGY,vol. 278, p. R1627 (2000); CURRENT OPINION IN CLINICAL NUTRITION ANDMETABOLIC CARE, vol. 2, p. 425 (1999); CURRENT RHEUMATOLOGY REPORTS,vol. 3, p. 101 (2001), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CAREMEDICINE, vol. 165, p. 1217 (2002).

It was recently found that, as a result of the study by the presentinventors, certain NPY receptor antagonists are useful for theprophylaxis or treatment of hypercholesterolemia, hyperlipidemia andarteriosclerosis (International application publication WO99/27965).

International application publications WO00/27845 (Patent literature 1)and WO01/14376 (Patent literature 2) disclose a variety of carboxamidederivatives, and mentions that the derivatives have excellent NPYreceptor antagonistic actions. In addition, international applicationpublication WO02/48152 (Patent literature 3) discloses a variety ofspiro[isobenzofuran-1,4′-piperidin]-3-one derivatives, and reports thatthe derivatives regulate NPY binding to NPY receptor. In thosepublications, however, there is no description of the compounds of thepresent invention.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a medicine having anNPY antagonist activity.

The present inventors have found that a compound of the formula (I):

(wherein Az is a group comprising a monocyclic azole or a bicyclicaromatic ring of the same or different fused azoles, which is optionallysubstituted by a substituent selected from the group consisting ofhalogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, loweralkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹;

Ar¹ is aryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, nitro, oxo,hydroxy, loweralkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-loweralkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio,lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl,lower alkanoylamino and -Q²-Ar²;

Ar² is aryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, cyano, loweralkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl;

Q¹ and Q² are independently a single bond, oxygen atom, carbonyl or—N(R³)—;

R¹and R² are independently hydrogen atom or lower alkyl, or R¹ and R²,taken together, form lower alkylene which may be interrupted by oxygenatom, sulfur atom or imino;

R³ is hydrogen atom or lower alkyl;

T, U, V and W are independently methine or nitrogen atom, said methinebeing optionally substituted by a substituent selected from the groupconsisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, loweralkoxy and halo-lower alkoxy, and at least two of T, U, V and W are saidmethine groups; and

X is nitrogen atom or methine), or a salt or ester thereof, has an NPYantagonist activity, particularly antagonist activity against NPY Y5receptor, and show excellent pharmacokinetics such as transport intobrain or transport to cerebrospinal fluid. Based on these findings, thepresent invention has been completed.

Compounds of the present invention (I) exhibit NPY antagonistic effectsespecially on NPY Y5 receptors and show excellent pharmacokinetics suchas transport into brain or transport to cerebrospinal fluid, etc., andthey are highly safe. Thus, they are useful for the treatment of variousdiseases related to NPY, for example, cardiovascular disorders such asangina, acute or congestive heart failure, myocardial infarction,hypertension, nephropathy, electrolyte abnormality, vasospasm,arteriosclerosis, etc.; central nervous system disorders such asbulimia, depression, anxiety, seizure, epilepsy, dementia, pain,alcoholism, drug withdrawal, circadian rhythm disorders, schizophrenia,memory impairment, sleep disorders, cognitive impairment, etc.;metabolicdiseases such as obesity, diabetes, hormone abnormality,hypercholesterolemia, hyperlipemia, gout, fatty liver, etc.; genital orreproductive disorders such as infertility, preterm labor, sexualdysfunction, etc.; gastro-intestinal disorders; respiratory disorder;inflammatory diseases or glaucoma, and the like; also for example,atherosclerosis; hypogonadism; hyperandrogenism; polycystic ovarysyndrome; hirsutism; gastro-intestinal motility disorder;obesity-related gastro-esophageal reflux; obesity hypoventilation(Pickwickian syndrome); sleep apnea; inflammation; systemic inflammationof the vasculature; osteoarthritis; insulin resistance;bronchoconstriction; alcohol preference; metabolic syndrome (syndromeX); Alzheimer's disease; cardiac hypertrophy; left ventricularhypertrophy; hypertriglyceridemia; low HDL cholesterol; cardiovasculardisorders such as coronary heart disease (CHD), cerebrovascular disease,stroke, peripheral vascular disease, and sudden death; gallbladderdiseases; cancer (breast, endometrial, colon); breathlessness;hyperuricemia; impaired fertility; low back pain; increased anestheticrisk, and the like; renal system diseases; renal abnormalities such asdysfunction in body fluid flow, abnormalities of materialtransportation, and renal failure; shock; arrhythmia; symptoms relatedto surge in sympathomimetic activity during or after operation oncoronary artery or gastrointestinal tracts; diseases related to brain orcentral nervous system, such as cerebral infarction, neurodegeneration,cerebral stroke, cerebrovascular spasm or cerebral hemorrhage; symptomsrelated to pain or nociception; diseases related to abnormalities ingastrointestinal motility or secretion, such as various ileuses, urinaryincontinence, and Crohn's disease; eating disorders such as anorexia andbulimia; inflammatory symptoms or diseases; asthma; bronchioleconstriction; or diseases related to abnormal secretion of hormones suchas luteinizing hormone, growthhormone, insulin, and luteotropic hormone.

Particularly, the compounds (I) of the present invention are useful forthe treatment of, for example, bulimia, obesity, diabetes.

The present invention relates to compounds of the formula (I), saltsthereof, esters thereof and their production or use.

The means of terms used in the present specification are defined andmore detailed description of this invention is described in thefollowing.

“Monocyclic azole” refers to a monocyclic azole comprising pyrrole,imidazole, pyrazole, triazole and tetrazole.

“Bicyclic aromatic ring of the same or different fused azoles” refers toa bicyclic aromatic ring wherein the said same or different azoles areortho-fused, including, for example, 1,5-dihydropyrrolo[2,3-c]pyrrole,1H-pyrrolo[1,2-b]pyrazole, 1,6-dihydropyrrolo[2,3-c]pyazole,1,4-dihydropyrrolo[3,2-c]pyrazole, 1H-pyrrolo[1,2-a]imidazole,1,5-dihydropyrrolo[3,4-d]imidazole,1,4-dihydropyrrolo[2,3-d][1,2,3]triazole,1H-pyrrolo[1,2-b][1,2,4]triazole, 1H-imidazo[1,2-b]pyrazole,1,4-dihydroimidazo[4,5-c]pyrazole, 1H-imidazo[1,2-a]imidazole,1,4-dihydroimidazo[4,5-d][1,2,3]triazole,1H-imidazo[1,2-b][1,2,4]triazole, 1H-pyrazolo[2,3-b]pyrazole,1H-pyrazolo[2,3-b][1,2,4]triazole,1H-1,2,4-triazolo[2,3-b][1,2,4]triazole or a tautomer thereof.

“Halogen” refers to fluorine, chlorine, bromine and iodine.

“Lower alkyl” refers to a straight-or branched-chain alkyl group havingone to six carbon atoms, and its examples are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl and the like.

“Halo-lower alkyl” refers to said lower alkyl substituted by identicallyor differently one, two or more, preferably one to three said halogenatom(s) at the substitutable, arbitrary position(s), and its examplesare fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,1,2-difluoroethyl, chloromethyl, 2-chloroethyl, 1,2-dichloroethyl,bromomethyl, iodomethyl and the like.

“Lower alkoxy” refers to straight- or branched-chain alkoxy having oneto six carbon atoms and its examples are methoxy, ethoxy, propoxy,isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy,isopentyloxy, hexyloxy, isohexyloxy and the like.

“Halo-lower alkoxy” refers to said lower alkoxy substituted byidentically or differently one, two or more, preferably one to threesaid halogen atom(s) at substitutable, arbitrary position(s), and itsexamples are fluoromethoxy, difluoromethoxy, trifluoromethoxy,2-fluoroethoxy, 1,2-difluoroethoxy, chloromethoxy, 2-chloroethoxy,1,2-dichloroethoxy, bromomethoxy, iodomethoxy and the like.

“Lower alkoxycarbonyl” refers to an alkoxycarbonyl group containing saidlower alkoxy, that is, an alkoxycarbonyl group having two to sevencarbon atoms, and its examples are methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl and the like.

“Lower alkylsulfonyl” refers to a straight- or branched-chainalkylsulfonyl group having one to six carbon atoms, and its examples aremethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl,pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl andthe like.

“Lower alkylsulfonyloxy” refers to a straight- or branched-chainalkylsulfonyloxy group having one to six carbon atoms, and its examplesare methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy,isopropylsulfonyloxy, butylsulfonyloxy, sec-butylsulfonyloxy,isobutylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy,isopentylsulfonyloxy, hexylsulfonyloxy, isohexylsulfonyloxy and thelike.

“Hydroxy-lower alkyl” refers to said lower alkyl substituted by one, twoor more, preferably one or two hydroxy at substitutable, arbitraryposition(s), and its examples are hydroxymethyl, 2-hydroxyethyl,1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl and thelike.

“Cyclo-lower alkyl” refers to a cycloalkyl group having three to sixcarbon atoms, and its examples are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

“Lower alkenyl” refers to a straight- or branched-chain alkenyl grouphaving two to six carbon atoms, and its examples are vinyl, 1-propenyl,2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl,1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-ethyl-1-ethenyl,2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl, 4-pentenyland the like.

“Lower alkylthio” refers to straight- or branched-chain alkylthio havingone to six carbon atoms, and its examples are methylthio, ethylthio,propylthio, isopropylthio, butylthio, sec-butylthio, isobutylthio,tert-butylthio, pentylthio, isopentylthio, hexylthio, isohexylthio andthe like.

“Lower alkanoyl” refers to an alkanoyl group containing said loweralkyl, that is, an alkanoyl group having two to seven carbon atoms, andits examples are acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl and the like.

“Lower alkanoylamino” refers to an amino group mono-substituted by saidlower alkanoyl, and its examples are acetylamino, propionylamino,butyrylamino, isobutyrylamino, valerylamino, isovalerylamino,pivaloylamino and the like.

“Aryl” refers to phenyl, naphthyl and the like.

“Heteroaryl” refers to 5- or 6-membered monocyclic heteroaromatic groupwhich contains one, two or more, preferably one to three hetero atom(s)identically or differently selected from the group consisting of oxygenatom, nitrogen atom and sulfur atom; or fused cyclic heteroaromaticgroup, where said monocyclic heteroaromatic group is fused with saidaryl group or fused each other with the same or different saidmonocyclic heteroaromatic group, and its examples are pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl,benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl,benzothiazolyl, benzoisothiazolyl, indazolyl, purinyl, quinolyl,isoquinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl,cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl and the like.

“Lower alkylamino” refers to an amino group mono-substituted by saidlower alkyl, and its examples are methylamino, ethylamino, propylamino,isopropylamino, butylamino, sec-butylamino, tert-butylamino and thelike.

“Di-lower alkylamino” refers to an amino group di-substituted by thesame or different said lower alkyl, and its examples are dimethylamino,diethylamino, ethylmethylamino, dipropylamino, methylpropylamino,diisopropylamino and the like.

“Lower alkylene which may be interrupted by oxygen atom, sulfur atom orimino” refers to an alkylene group of C2 to C5, which is not intervenedor interrupted by one, two or more, preferably one oxygen atom, sulfuratom or imino at optional and intervention capable positions of saidalkylene chain, and its examples are ethylene, trimethylene,tetramethylene, pentamethylene, 2-oxatetramethylene,2-oxapentamethylene, 3-oxapentamethylene, 2-thiatetramethylene,2-thiapentamethylene, 3-thiapentamethylene, 2-azatetramethylene,2-azapentamethylene, 3-azapentamethylene and the like.

“Aralkyl” refers to said lower alkyl substituted by one, two or more,preferably one said aryl at substitutable, arbitrary position(s), andits examples are benzyl, 1-phenylethyl, phenethyl, 1-naphthylmethyl,2-naphthylmethyl and the like. The esters of compounds of formula (I)refer to, for example, the pharmaceutically acceptable, common esters ofsaid carboxyl group when the compound has a carboxyl group, and examplesthereof are esters with lower alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,cyclopropyl, cyclobutyl, cyclopentyl), esters with aralkyl (e.g. benzyl,phenethyl), esters with lower alkenyl (e.g. alkyl, 2-butenyl), esterswith lower alkoxy-lower alkyl (e.g. methoxymethyl, 2-methoxyethyl,2-ethoxyethyl), esters with lower alkanoyloxy-lower alkyl (e.g.acetoxymethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl), esters with loweralkoxycarbonyl-lower-alkyl (e.g. methoxycarbonylmethyl,isopropoxycarbonylmethyl), esters with carboxy-lower alkyl (e.g.carboxymethyl), esters with lower alkoxycarbonyloxy-lower alkyl (e.g.1-(ethoxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl), esterswith carbamoyloxy-lower alkyl (e.g. carbamoyloxymethyl), esters withphthalidyl, esters with (5-substituted-2-oxo-1,3-dioxol-4-yl)methyl(e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) and the like.

The salts of compounds of formula (I) refer to the pharmaceuticallyacceptable, common salts, and examples thereof are base addition salt tosaid carboxyl group when the compound has a carboxyl group, or acidaddition salt to said amino or basic heterocyclyl when the compound hasan amino or basic heterocyclyl group and the like.

Said base addition salts include salts with alkali metals (e.g. sodium,potassium); salts with alkaline earthmetals (e.g. calcium, magnesium);ammonium salts; salts with organic amines (e.g. trimethylamine,triethylamine, dicyclohexylamine, ethanolamine, diethanolamine,triethanolamine, procaine, N,N′-dibenzylethylenediamine) and the like.

Said acid addition salts include salts with inorganic acids (e.g.hydrochloricacid, sulfuricacid, nitricacid, phosphoric acid, perchloricacid), salts with organic acids (e.g. maleic acid, fumaric acid,tartaric acid, citric acid, ascorbic acid, trifluoroacetic acid), saltswith sulfonic acids (e.g. methanesulfonic acid, isethionic acid,benzenesulfonic acid, p-toluenesulfonic acid) and the like.

“An agent for treatment” refers to a medicament which is employed forthe treatment and/or prophylaxis of various diseases.

In order to disclose the aforesaid compounds of the general formula (I)of the present invention more specifically, the various symbols used inthe formula (I) are explained in more detail by presenting preferredembodiments.

Az is a group comprising a monocyclic azole or a bicyclic aromatic ringof the same or different fused azoles, which is optionally substitutedby a substituent selected from the group consisting of halogen, cyano,lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy,lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy,—N(R¹)R² and -Q¹-Ar¹.

“A group comprising a monocyclic azole or bicyclic aromatic ring of thesame or different azoles, which is optionally substituted by asubstituent selected from the group consisting of halogen, cyano,loweralkyl, halo-loweralkyl, hydroxy, lower alkoxy, halo-lower alkoxy,lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy,—N(R¹)R² and -Q¹-Ar¹″ means an unsubstituted monocyclic azole describedabove, a monocyclic azole having a substituent at substitutable,arbitrary position(s), a bicyclic aromatic ring of said unsubstitutedsame or different fused azoles, or a bicyclic aromatic ring of said sameor different fused azoles having one, two or more substituent(s),preferably one or two substituents, selected from the group consistingof halogen, cyano, lower alkyl, halo-loweralkyl, hydroxy, lowralkoxy,halo-loweralkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, loweralkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹″ at substitutable, arbitraryposition(s).

Halogen as said substituent preferably includes, for example, fluorine,chlorine and the like.

Lower alkyl as said substituent preferably includes, for example,methyl, ethyl and the like.

Halo-lower alkyl as said substituent preferably includes, for example,difluoromethyl, trifluoromethyl and the like.

Lower alkoxy as said substituent preferably includes, for example,methoxy, ethoxy and the like.

Halo-lower alkoxy as said substituent preferably includes, for example,difluoromethoxy, trifluoromethoxy and the like.

Lower alkoxycarbonyl as said substituent preferably includes, forexample, methoxycarbonyl, ethoxycarbonyl and the like.

Lower alkylsulfonyl as said substituent preferably includes, forexample, methylsulfonyl, ethylsulfonyl and the like.

Lower alkylsulfonyloxy as said substituent preferably includes, forexample, methylsulfonyloxy, ethylsulfonyloxy and the like.

In a group of the formula: —N(R¹)R² as said substituent, R¹ and R² areindependently hydrogen atom or lower alkyl, or R¹ and R², takentogether, form lower alkylene which may be interrupted by oxygen atom,sulfur atom or imino.

Lower alkyl as R¹ or R² preferably includes, for example, methyl, ethyl,propyl and the like.

“Lower alkylene which may be interrupted by oxygen atom, sulfur atom orimino” formed by taking R¹and R² together preferably includespentamethylene, 3-oxapentamethylene and the like, and when takentogether with the adjacent nitrogen atom, it forms piperidino,morpholino and the like.

The preferred embodiment of R¹ and R² includes the case where at leastone of R¹ or R² is lower alkyl, or the case where R¹ and R², takentogether, form lower alkylene which may be interrupted by oxygen atom,sulfur atom or imino.

Thus, a group of the formula: —N(R¹)R² as said substituent includes, forexample, amino, methylamino, ethylamino, propylamino, dimethylamino,diethylamino, ethylmethylamino, 1-azetidinyl, 1-pyrrolidinyl,piperidino, morpholino, thiomorpholino, 1-piperazinyl and the like,among which preferred are methylamino, dimethylamino, piperidino,morpholino and the like.

In a group of the formula: -Q¹-Ar¹ as said substituent, Ar¹ is aryl orheteroaryl, any of which is optionally substituted by a substituentselected from the group consisting of halogen, nitro, oxo, hydroxy,lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl,lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, loweralkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkanoylamino and -Q²-Ar²; and Q¹ is a single bond, oxygen atom,carbonyl or —N(R³)—.

“Aryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, nitro, oxo,hydroxy, lower alkyl, halo-lower alkyl, hydroxyl-lower alkyl,cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, loweralkylthio, lower alkyl sulfonyl, carboxyl, lower alkanoyl, loweralkoxycarbonyl, lower alkanoylamino and -Q²-Ar²″ includes anunsubstituted aryl group described above, an unsubstituted heteroarylgroup described above, an aryl group described above or a heteroarylgroup, the last two groups optionally having one, two or more,preferably one or two substituents, which are the same or different,selected from the group consisting of halogen, nitro, oxo, hydroxy,lower alkyl, halo-loweralkyl, hydroxy-loweralkyl, cyclo-loweralkyl,loweralkenyl, loweralkoxy, halo-loweralkoxy, loweralkylthio, loweralkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkanoylamino and -Q²-Ar².

Halogen as said substituent preferably includes, for example, fluorine,chlorine, bromine and the like.

Lower alkyl as said substituent preferably includes, for example,methyl, ethyl, propyl, isopropyl and the like.

Halo-lower alkyl as said substituent preferably includes, for example,difluoromethyl, trifluoromethyl and the like.

Hydroxy-lower alkyl as said substituent preferably includes, forexample, hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl and thelike.

Cyclo-lower alkyl as said substituent preferably includes, for example,cyclopropyl, cyclobutyl and the like.

Lower alkenyl as said substituent preferably includes, for example,vinyl, 1-propenyl, 2-methyl-1-propenyl and the like.

Lower alkoxy as said substituent preferably includes, for example,methoxy, ethoxy and the like.

Halo-lower alkoxy as said substituent preferably includes, for example,fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.

Lower alkylthio as said substituent preferably includes, for example,methylthio, ethylthio and the like.

Lower alkylsulfonyl as said substituent preferably includes, forexample, methylsulfony, ethylsulfonyl, propylsulfonyl and the like.

Lower alkanoyl as said substituent preferably includes, for example,acetyl, propionyl and the like.

Lower alkoxycarbonyl as said substituent preferably includes, forexample, methoxycarbonyl, ethoxycarbonyl and the like.

Lower alkanoylamino as said substituent preferably includes, forexample, acetylamino, propanoylamino and the like.

In a group of the formula: -Q²-Ar² as said substituent, Ar²is aryl orheteroaryl, any of which is optionally substituted by a substituentselected from the group consisting of halogen, cyano, lower alkyl,halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-loweralkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl;and Q² is a single bond, oxygen atom, carbonyl or —N(R³)—.

“Aryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, cyano, loweralkyl, halo-lower alkyl, hydroxyl-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl” refers to an unsubstituted aryl group described above, anunsubstituted heteroaryl group described above, an aryl group describedabove or a heteroaryl group described above, the last two groups beingoptionally substituted by one, two or more, preferably one or twosubstituent (s) identically or differently selected from the groupconsisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-loweralkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino,di-lower alkylamino, lower alkanoyl and aryl at substitutable, arbitraryposition(s).

Halogen as said substituent preferably includes, for example, fluorine,chlorine and the like.

Lower alkyl as said substituent preferably includes, for example,methyl, ethyl, propyl, isopropyl and the like.

Halo-lower alkyl as said substituent preferably includes, for example,difluoromethyl, trifluoromethyl and the like.

Hydroxy-lower alkyl as said substituent preferably includes, forexample, hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl and thelike.

Lower alkoxy as said substituent preferably includes, for example,methoxy, ethoxy and the like.

Halo-lower alkoxy as said substituent preferably includes, for example,fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.

Lower alkylamino as said substituent preferably includes, for example,methylamino, ethylamino and the like.

Di-lower alkylamino as said substituent preferably includes, forexample, dimethylamino, diethylamino and the like.

Lower alkanoyl as said substituent preferably includes, for example,acetyl, proionyl and the like.

Aryl as said substituent preferably includes, for example, phenyl.

Substituent of Ar² preferably includes, for example, halogen, cyano,lower alkyl, halo-lower alkyl, hydroxyl-lower alkyl, hydroxy, halo-loweralkoxy and the like.

Aryl represented by Ar²preferably includes, for example, phenyl, andheteroaryl represented by Ar² preferably includes pyridyl, quinolyl andthe like.

In a group of the formula —N(R³)— of Q¹ and Q², R³is hydrogen atom orlower alkyl.

R³ preferably includes, for example, hydrogen atom, methyl, ethyl andthe like.

Q² preferably includes, for example, a single bond.

Substituent of Ar¹ includes, for example, halogen, hydroxy, lower alkyl,halo-lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyl, -Q²-Ar²and the like, more preferably halogen, hydroxy, halo lower alkyl, loweralkoxy, -Q²-Ar²— and the like.

Aryl as Ar¹ preferably includes, for example, phenyl, naphthyl and thelike, and heteroaryl as Ar¹ preferably includes, for example,imidazolyl, furyl, thienyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,benzofuranyl, quinolyl, isoquinolyl, and the like, more preferablypyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl andthe like.

Consequently, Ar¹ includes, for example, phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 2-chloro-4-fluorophenyl,2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl,2-bromo-4-fluorophenyl, 2-bromo-5-fluorophenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 5-fluoro-2-methylphenyl,3-fluoromethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 5-fluoro-2-methoxyphenyl, 3-fluoromethoxyphenyl,2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl,2-hydroxy-4-fluorophenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 1-naphthyl, 2-fluoro-1-naphthyl,3-fluoro-1-naphthyl, 4-fluoro-1-naphthyl, 5-fluoro-1-naphthyl,6-fluoro-1-naphthyl, 7-fluoro-1-naphthyl, 8-fluoro-1-naphthyl,2-naphthyl, 1-fluoro-2-naphthyl, 3-fluoro-2-naphthyl,4-fluoro-2-naphthyl, 5-fluoro-2-naphthyl, 6-fluoro-2-naphthyl,7-fluoro-2-naphthyl, 8-fluoro-2-naphthyl, 2-imidazolyl,4-phenylimidazol-2-yl, 4-(2-fluorophenyl)imidazol-2-yl,4-(3-fluorophenyl)imidazol-2-yl, 4-(4-fluorophenyl)imidazol-2-yl,2-furyl, 4-phenylfuran-2-yl, 4-(2-fluorophenyl)furan-2-yl,4-(3-fluorophenyl)furan-2-yl, 4-(4-fluorophenyl)furan-2-yl, 2-thienyl,4-phenylthiophen-2-yl, 4-(2-fluorophenyl)thiophen-2-yl,4-(3-fluorophenyl)thiophen-2-yl, 4-(4-fluorophenyl)thiophen-2-yl,3-pyrazolyl, 1-phenylpyrazol-3-yl, 1-(2-fluorophenyl)pyrazol-3-yl,1-(3-fluorophenyl)pyrazol-3-yl, 1-(4-fluorophenyl)pyrazol-3-yl,5-phenylpyrazol-3-yl, 5-(2-fluorophenyl)pyrazol-3-yl,5-(3-fluorophenyl)pyrazol-3-yl, 5-(4-fluorophenyl)pyrazol-3-yl,4-pyrazolyl, 1-phenylpyrazol-4-yl, 1-(2-fluorophenyl)pyrazol-4-yl,1-(3-fluorophenyl)pyrazol-4-yl, 1-(4-fluorophenyl)pyrazol-4-yl,1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 2-phenyl-1,3,4-oxadiazol-5-yl,1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-phenyl-1,3,4-thiadiazol-5-yl, 2-pyridyl,3-phenylpyridin-2-yl, 4-phenylpyridin-2-yl, 5-phenylpyridin-2-yl,6-phenylpyridin-2-yl, 3-pyridyl, 2-phenylpyridin-3-yl,4-phenylpyridin-3-yl, 5-phenylpyridin-3-yl, 4-pyridyl,2-phenylpyridin-4-yl; 3-phenylpyridin-4-yl, 2-phenylpyridin-5-yl,6-fluoro-2-pyridyl, 2-fluoro-4-pyridyl, 2-fluoro-5-pyridyl,5-fluoro-2-pyridyl, 2-pyrimidinyl, 4-phenylpyrimidin-2-yl,5-phenylpyrimidin-2-yl, 4-pyrimidinyl, 2-phenylpyrimidin-4-yl,2-(2-fluorophenyl)pyrimidin-4-yl, 2-(4-fluorophenyl)pyrimidin-4-yl,5-phenylpyrimidin-4-yl, 6-phenylpyrimidin-4-yl, 5-pyrimidinyl,2-phenylpyrimidin-5-yl, 4-phenylpyrimidin-5-yl, 2-pyrazinyl,3-phenylpyrazin-2-yl, 5-phenylpyrazin-2-yl, 6-phenylpyrazin-2-yl,4-benzo[b]furanyl, 5-benzo[b]furanyl, 7-benzo[b]furanyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, and the like, and among those, Ar¹ preferably includesphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-methoxyphenyl, 2-difluoromethoxyphenyl,3-difluoromethoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-naphthyl,3-biphenylyl, 4-biphenylyl, 1-phenylpyrazol-3-yl, 1-phenylpyrazol-4-yl,4-phenylpyridin-2-yl, 6-phenylpyridin-2-yl, 5-phenylpyridin-3-yl,2-phenylpyridin-4-yl, 6-fluoro-2-pyridyl, 2-fluoro-5-pyridyl,5-fluoro-2-pyridyl, 2-phenylpyrimidin-4-yl,2-(2-fluorophenyl)pyrimidin-4-yl, 2-(4-fluorbphenyl)pyrimidin-4-yl,6-phenylpyrimidin-4-yl, 6-phenylpyrazin-2-yl, 2-quinolyl, 3-quinolyl,3-isoquinolyl, 3-biphenylyl, 4-biphenylyl, and the like.

Q¹ includes, for example, a single bond, an oxygen atom, —N(R³)— and thelike, preferably a single bond.

Substituent of a monocyclic azole, or a bicyclic aromatic ring of thesame or different fused azoles, represented by Az, includes, forexample, halogen, halo-lower alkyl, lower alkoxycarbonyl, —N(R¹)R²,-Q¹-Ar¹ and the like, preferably -Q¹-Ar¹ and the like. Az is preferablya monocyclic azole or a bicyclic aromatic ring of the heretoforementioned same or different fused azoles, which bears -Q¹-Ar¹.

The monocyclic azole of Az preferably includes, for example,2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yland the like, represented by the following formulae (a).

The bicyclic aromatic ring group of the same or different fused azolesrepresented by Az preferably includes, for example, groups representedby the following formulae (b);

that is, 5H-imidazo[1,2-b]pyrazol-6-yl,1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,3H-imidazo[1,2-b][1,2,4]triazol-2-yl,1H-1,2,4-triazolo[2,3-b][1,2,4]triazol-2-yl,2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,2,4-dihydroimidazo[4,5-c]pyrazol-5-yl and the like, preferably1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,2,4-dihydroimidazo[4,5-c]pyrazol-5-yl and the like.

More specifically, an optionally substituted monocyclic azole of Az inthe formula (I) preferably includes, for example, groups represented bythe formulae (a₁):

wherein Y is hydrogen atom, halogen, cyano, lower alkyl, halo-loweralkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl,lower alkylsulfonyl, lower alkylsulfonyloxy —N(R¹)R² or -Q¹-Ar¹; andAr¹, Q¹, R¹ and R² have each the same meaning as defined above.

An optionally substituted bicyclic aromatic ring group of the same ordifferent fused azoles represented by Az in the formula (I) preferablyincludes, for example, groups represented by the formulae (b₁):

wherein Y has the same meaning as defined above, and the like.

In the above formula (a₁) or (b₁), Y preferably includes -Q¹-Ar¹.

In more detail, Az preferably includes, for example,

-   4-phenyl-1H-imidazol-2-yl,-   4,5-diphenyl-1H-imidazol-2-yl,-   4-methyl-5-phenyl-1H-imidazol-2-yl,-   4-(2-fluorophenyl)-1H-imidazol-2-yl,-   4-(3-fluorophenyl)-1H-imidazol-2-yl,-   4-(4-fluorophenyl)-1H-imidazol-2-yl,-   4-(2,4-difluorophenyl)-1H-imidazol-2-yl,-   4-(2,5-difluorophenyl)-1H-imidazol-2-yl,-   4-(3,5-difluorophenyl)-1H-imidazol-2-yl,-   4-(2-chlorophenyl)-1H-imidazol-2-yl,-   4-(3-chlorophenyl)-1H-imidazol-2-yl,-   4-(3-bormophenyl)-1H-imidazol-2-yl,-   4-(4-bormophenyl)-1H-imidazol-2-yl,-   4-(2-trifluoromethylphenyl)-1H-imidazol-2-yl,-   4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl,-   4-(4-trifluoromethylphenyl)-1H-imidazol-2-yl,-   4-(3-methoxyphenyl)-1H-imidazol-2-yl,-   4-(2-difluoromethoxyphenyl)-1H-imidazol-2-yl,-   4-(3-difluoromethoxyphenyl)-1H-imidazol-2-yl,-   4-(3-hydroxyphenyl)-1H-imidazol-2-yl,-   4-(4-hydroxyphenyl)-1H-imidazol-2-yl,-   4-(2-naphthyl)-1H-imidazol-2-yl,-   4-(1-phenylpyrazol-3-yl)-1H-imidazol-2-yl,-   4-(1-phenylpyrazol-4-yl)-1H-imidazol-2-yl,-   4-(4-phenylpyridin-2-yl)-1H-imidazol-2-yl,-   4-(6-phenylpyridin-2-yl)-1H-imidazol-2-yl,-   4-(5-phenylpyridin-3-yl)-1H-imidazol-2-yl,-   4-(2-phenylpyridin-4-yl)-1H-imidazol-2-yl,-   4-(6-fluoropyridin-2-yl)-1H-imidazol-2-yl,-   4-(2-fluoropyridin-5-yl)-1H-imidazol-2-yl,-   4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl,-   4-(4-fluorophenyl)-5-(3-pyridyl)-1H-imidazol-2-yl,-   4-(2-phenylpyrimidin-4-yl)-1H-imidazol-2-yl,-   4-(6-phenylpyrimidin-4-yl)-1H-imidazol-2-yl,-   4-(6-phenylpyrazin-2-yl)-1H-imidazol-2-yl,-   4-(2-quinolyl)-1H-imidazol-2-yl,-   4-(3-quinolyl)-1H-imidazol-2-yl,-   4-(3-isoquinolyl)-1H-imidazol-2-yl,-   4-(3-biphenylyl)-1H-imidazol-2-yl,-   4-(4-biphenylyl)-1H-imidazol-2-yl,-   2-phenyl-1H-imidazol-4-yl,-   2-(2-fluorophenyl)-1H-imidazol-4-yl,-   2-(3-fluorophenyl)-1H-imidazol-4-yl,-   2-(4-fluorophenyl)-1H-imidazol-4-yl,-   2-(2,4-difluorophenyl)-1H-imidazol-4-yl,-   2-(2,5-difluorophenyl)-1H-imidazol-4-yl,-   2-(3,5-difluorophenyl)-1H-imidazol-4-yl,-   2-(2-chlorophenyl)-1H-imidazol-4-yl,-   2-(3-chlorophenyl)-1H-imidazol-4-yl,-   2-(3-bromophenyl)-1H-imidazol-4-yl,-   2-(4-bromophenyl)-1H-imidazol-4-yl,-   2-(2-trifluoromethylphenyl)-1H-imidazol-4-yl,-   2-(3-trifluoromethylphenyl)-1H-imidazol-4-yl,-   2-(4-trifluoromethylphenyl)-1H-imidazol-4-yl,-   2-(3-methoxyphenyl)-1H-imidazol-4-yl,-   2-(2-difluoromethoxyphenyl)-1H-imidazol-4-yl,-   2-(3-difluoromethoxyphenyl)-1H-imidazol-4-yl,-   2-(3-hydroxyphenyl)-1H-imidazol-4-yl,-   2-(4-hydroxyphenyl)-1H-imidazol-4-yl,-   2-(2-naphthyl)-1H-imidazol-4-yl,-   2-(1-phenylpyrazol-3-yl)-1H-imidazol-4-yl,-   2-(1-phenylpyrazol-4-yl)-1H-imidazol-4-yl,-   2-(4-phenylpyridin-2-yl)-1H-imidazol-4-yl,-   2-(6-phenylpyridin-2-yl)-1H-imidazol-4-yl,-   2-(5-phenylpyridin-3-yl)-1H-imidazol-4-yl,-   2-(2-phenylpyridin-4-yl)-1H-imidazol-4-yl,-   2-(6-fluoropyridin-2-yl)-1H-imidazol-4-yl,-   2-(2-fluoropyridin-5-yl)-1H-imidazol-4-yl,-   2-(5-fluoropyridin-2-yl)-1H-imidazol-4-yl,-   2-(2-phenylpyrimidin-4-yl)-1H-imidazol-4-yl,-   2-(6-phenylpyrimidin-4-yl)-1H-imidazol-4-yl,-   2-(6-phenylpyrazin-2-yl)-1H-imidazol-4-yl,-   2-(2-quinolyl)-1H-imidazol-4-yl,-   2-(3-quinolyl)-1H-imidazol-4-yl,-   2-(3-isoquinolyl)-1H-imidazol-4-yl,-   2-(3-biphenylyl)-1H-imidazol-4-yl,-   2-(4-biphenylyl)-1H-imidazol-4-yl,-   5-phenyl-1H-pyrazol-3-yl,-   5-(2-fluorophenyl)-1H-pyrazol-3-yl,-   5-(3-fluorophenyl)-1H-pyrazol-3-yl,-   5-(4-fluorophenyl)-1H-pyrazol-3-yl,-   5-(2,4-difluorophenyl)-1H-pyrazol-3-yl,-   5-(2,5-difluorophenyl)-1H-pyrazol-3-yl,-   5-(3,5-difluorophenyl)-1H-pyrazol-3-yl,-   5-(2-chlorophenyl)-1H-pyrazol-3-yl,-   5-(3-chlorophenyl)-1H-pyrazol-3-yl,-   5-(3-bromophenyl)-1H-pyrazol-3-yl,-   5-(4-bromophenyl)-1H-pyrazol-3-yl,-   5-(2-trifluoromethylphenyl)-1H-pyrazol-3-yl,-   5-(3-trifluoromethylphenyl)-1H-pyrazol-3-yl,-   5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl,-   5-(3-methoxyphenyl)-1H-pyrazol-3-yl,-   5-(2-difluoromethoxyphenyl)-1H-pyrazol-3-yl,-   5-(3-difluoromethoxyphenyl)-1H-pyrazol-3-yl,-   5-(3-hydroxyphenyl)-1H-pyrazol-3-yl,-   5-(4-hydroxyphenyl)-1H-pyrazol-3-yl,-   5-(2-naphthyl)-1H-pyrazol-3-yl,-   5-(l-phenylpyrazol-3-yl)-1H-pyrazol-3-yl,-   5-(4-phenylpyrazol-4-yl)-1H-pyrazol-3-yl,-   5-(4-phenylpyridin-2-yl)-1H-pyrazol-3-yl,-   5-(6-phenylpyridin-2-yl)-1H-pyrazol-3-yl,-   5-(5-phenylpyridin-3-yl)-1H-pyrazol-3-yl,-   5-(2-phenylpyridin-4-yl)-1H-pyrazol-3-yl,-   5-(6-fluoropyridin-2-yl)-1H-pyrazol-3-yl,-   5-(2-fluoropyridin-5-yl)-1H-pyrazol-3-yl,-   5-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl,-   5-(2-phenylpyrimidin-4-yl)-1H-pyrazol-3-yl,-   5-[2-(2-fluorophenyl)pyrimidin-4-yl]-1H-pyrazol-3-yl,-   5-[2-(4-fluorophenyl)pyrimidin-4-yl]-1H-pyrazol-3-yl,-   5-(6-phenylpyrimidin-4-yl)-1H-pyrazol-3-yl,-   5-(6-phenylpyrazin-2-yl)-1H-pyrazol-3-yl,-   5-(2-quinolyl)-1H-pyrazol-3-yl,-   5-(3-quinolyl)-1H-pyrazol-3-yl,-   5-(3-isoquinolyl)-1H-pyrazol-3-yl,-   5-(3-biphenylyl)-1H-pyrazol-3-yl,-   5-(4-biphenylyl)-1H-pyrazol-3-yl,-   5-phenyl-1H-1,2,4-triazol-3-yl,-   5-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(2,4-difluorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(2,5-difluorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(3,5-difluorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-bromophenyl)-1H-1,2,4-triazol-3-yl,-   5-(4-bromophenyl)-1H-1,2,4-triazol-3-yl,-   5-(2-trifluoromethylphenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-trifluoromethylphenyl)-1H-1,2,4-triazol-3-yl,-   5-(4-trifluoromethylphenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-methoxyphenyl)-1H-1,2,4-triazol-3-yl,-   5-(2-difluoromethoxyphenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-difluoromethoxyphenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-hydroxyphenyl)-1H-1,2,4-triazol-3-yl,-   5-(4-hydroxyphenyl)-1H-1,2,4-triazol-3-yl,-   5-(2-naphthyl)-1H-1,2,4-triazol-3-yl,-   5-(l-phenylpyrazol-3-yl)-1H-1,2,4-triazol-3-yl,-   5-(1-phenylpyrazol-4-yl)-1H-1,2,4-triazol-3-yl,-   5-(4-phenylpyridin-2-yl)-1H-1,2,4-triazol-3-yl,-   5-(6-phenylpyridin-2-yl)-1H-1,2,4-triazol-3-yl,-   5-(5-phenylpyridin-3-yl)-1H-1,2,4-triazol-3-yl,-   5-(2-phenylpyridin-4-yl)-1H-1,2,4-triazol-3-yl,-   5-(6-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl,-   5-(2-fluoropyridin-5-yl)-1H-1,2,4-triazol-3-yl,-   5-(5-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl,-   5-(2-phenylpyrimidin-4-yl)-1H-1,2,4-triazol-3-yl,-   5-(6-phenylpyrimidin-4-yl)-1H-1,2,4-triazol-3-yl,-   5-(6-phenylpyrazin-2-yl)-1H-1,2,4-triazol-3-yl,-   5-(2-quinolyl)-1H-1,2,4-triazol-3-yl,-   5-(3-quinolyl)-1H-1,2,4-triazol-3-yl,-   5-(3-isoquinolyl)-1H-1,2,4-triazol-3-yl,-   5-(3-biphenylyl)-1H-1,2,4-triazol-3-yl,-   5-(4-biphenylyl)-1H-1,2,4-triazol-3-yl,-   6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(4-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2,4-difluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2,5-difluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3,5-difluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2-chlorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-chlorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-bromophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(4-bromophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2-trifluoromethylphenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-trifluoromethylphenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(4-trifluoromethylphenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-methoxyphenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2-difluoromethoxyphenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-difluoromethoxyphenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-hydroxyphenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(4-hydroxyphenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(6-fluoropyridin-2-yl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2-fluoropyridin-5-yl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(5-fluoropyridin-2-yl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   5-phenyl-1H-imidazo[1,2-b][1,2,4]triazol-2-yl,-   2-phenyl-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(2-fluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3-fluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(4-fluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(2,4-difluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(2,5-difluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3,5-difluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(2-chlorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3-chlorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3-bromophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(4-bromophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(2-trifluoromethylphenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3-trifluoromethylphenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(4-trifluoromethylphenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3-methoxyphenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(2-difluoromethoxyphenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3-difluoromethoxyphenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3-hydroxyphenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(4-hydroxyphenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(6-fluoropyrdin-2-yl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(2-fluoropyrdin-5-yl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(5-fluoropyrdin-2-yl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-phenyl-1H-imidazo[1,2-b]pyrazol-6-yl,-   2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(2-fluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3-fluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(4-fluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(2,4-difluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(2,5-difluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3,5-difluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(2-chlorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3-chlorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3-bromophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(4-bromophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(2-trifluoromethylphenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3-trifluoromethylphenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(4-trifluoromethylphenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3-methoxyphenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(2-difluoromethoxyphenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3-difluoromethoxyphenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3-hydroxyphenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(4-hydroxyphenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(6-fluoropyridin-2-yl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(2-fluoropyridin-5-yl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(5-fluoropyridin-2-yl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   6-phenyl-1H-[1,2,4]triazolo[2,3-b][1,2,4]triazol-2-yl, and the like

Among those groups mentioned above, more preferable examples of Az are

-   4,5-diphenyl-1H-imidazol-2-yl,-   4-methyl-5-phenyl-1H-imidazol-2-yl,-   4-(3,5-difluorophenyl)-1H-imidazol-2-yl,-   4-(3-chlorophenyl)-1H-imidazol-2-yl,-   4-(3-bormophenyl)-1H-imidazol-2-yl,-   4-(4-bormophenyl)-1H-imidazol-2-yl,-   4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl,-   4-(3-methoxyphenyl)-1H-imidazol-2-yl,-   4-(3-difluoromethoxyphenyl)-1H-imidazol-2-yl,-   4-(2-naphthyl)-1H-imidazol-2-yl,-   4-(1-phenylpyrazol-3-yl)-1H-imidazol-2-yl,-   4-(2-phenylpyridin-4-yl)-1H-imidazol-2-yl,-   4-(4-fluorophenyl)-5-(3-pyridyl)-1H-imidazol-2-yl,-   4-(2-phenylpyrmidin-4-yl)-1H-imidazol-2-yl,-   4-(6-phenylpyrazin-2-yl)-1H-imidazol-2-yl,-   4-(2-quinolyl)-1H-imidazol-2-yl,-   4-(3-quinolyl)-1H-imidazol-2-yl,-   4-(3-isoquinolyl)-1H-imidazol-2-yl,-   4-(3-biphenylyl)-1H-imidazol-2-yl,-   4-(4-biphenylyl)-1H-imidazol-2-yl,-   2-(3,5-difluorophenyl)-1H-imidazol-4-yl,-   2-(3-chlorophenyl)-1H-imidazol-4-yl,-   2-(3-bromophenyl)-1H-imidazol-4-yl,-   2-(4-bromophenyl)-1H-imidazol-4-yl,-   2-(3-trifluoromethylphenyl)-1H-imidazol-4-yl,-   2-(3-difluoromethoxyphenyl)-1H-imidazol-4-yl,-   2-(2-naphthyl)-1H-imidazol-4-yl,-   2-(l-phenylpyrazol-3-yl)-1H-imidazol-4-yl,-   2-(2-phenylpyridin-4-yl)-1H-imidazol-4-yl,-   2-(2-phenylpyrimidin-4-yl)-1H-imidazol-4-yl,-   2-(6-phenylpyrazin-2-yl)-1H-imidazol-4-yl,-   2-(2-quinolyl)-1H-imidazol-4-yl,-   2-(3-quinolyl)-1H-imidazol-4-yl,-   2-(3-isoquinolyl)-1H-imidazol-4-yl,-   2-(3-biphenylyl)-1H-imidazol-4-yl,-   5-(3,5-difluorophenyl)-1H-pyrazol-3-yl,-   5-(3-chlorophenyl)-1H-pyrazol-3-yl,-   5-(3-bromophenyl)-1H-pyrazol-3-yl,-   5-(4-bromophenyl)-1H-pyrazol-3-yl,-   5-(3-trifluoromethylphenyl)-1H-pyrazol-3-yl,-   5-(3-difluoromethoxyphenyl)-1H-pyrazol-3-yl,-   5-(2-naphthyl)-1H-pyrazol-3-yl,-   5-(1-phenylpyrazol-3-yl)-1H-pyrazol-3-yl,-   5-(2-phenylpyridin-4-yl)-1H-pyrazol-3-yl,-   5-(2-phenylpyrimidin-4-yl)-1H-pyrazol-3-yl,-   5-(6-phenylpyrazin-2-yl)-1H-pyrazol-3-yl,-   5-(2-quinolyl)-1H-pyrazol-3-yl,-   5-(3-quinolyl)-1H-pyrazol-3-yl,-   5-(3-isoquinolyl)-1H-pyrazol-3-yl,-   5-(3-biphenylyl)-1H-pyrazol-3-yl,-   5-(3,5-difluorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-bromophenyl)-1H-1,2,4-triazol-3-yl,-   5-(4-bromophenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-trifluoromethylphenyl)-1H-1,2,4-triazol-3-yl,-   5-(3-difluoromethoxyphenyl)-1H-1,2,4-triazol-3-yl,-   5-(2-naphthyl)-1H-1,2,4-triazol-3-yl,-   5-(1-phenylpyrazol-3-yl)-1H-1,2,4-triazol-3-yl,-   5-(2-phenylpyridin-4-yl)-1H-1,2,4-triazol-3-yl,-   5-(2-phenylpyrimidin-4-yl)-1H-1,2,4-triazol-3-yl,-   5-(6-phenylpyrazin-2-yl)-1H-1,2,4-triazol-3-yl,-   5-(2-quinolyl)-1H-1,2,4-triazol-3-yl,-   5-(3-quinolyl)-1H-1,2,4-triazol-3-yl,-   5-(3-isoquinolyl)-1H-1,2,4-triazol-3-yl,-   5-(3-biphenylyl)-1H-1,2,4-triazol-3-yl,-   6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(4-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   5-phenyl-1H-imidazo[1,2-b][1,2,4]triazol-2-yl,-   2-phenyl-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(2-fluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(3-fluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-(4-fluorophenyl)-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-phenyl-1H-imidazo[1,2-b]pyrazol-6-yl,-   2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(2-fluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(3-fluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   2-(4-fluorophenyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,-   6-phenyl-1H-[1,2,4]triazolo[2,3-b][1,2,4]triazol-2-yl and the like,    and especially preferred are-   4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl,-   4-(2-naphthyl)-1H-imidazol-2-yl,-   4-(3-biphenylyl)-1H-imidazol-2-yl,-   2-(3-trifluoromethylphenyl)-1H-imidazol-4-yl,-   2-(2-naphthyl)-1H-imidazol-4-yl,-   2-(3-biphenylyl)-1H-imidazol-4-yl,-   5-(3,5-difluorophenyl)-1H-pyrazol-3-yl,-   5-(3-chlorophenyl)-1H-pyrazol-3-yl,-   5-(3-bromophenyl)-1H-pyrazol-3-yl,-   3-(4-bromophenyl)-1H-pyrazol-3-yl,-   5-(3-trifluoromethylphenyl)-1H-pyrazol-3-yl,-   5-(3-difluoromethoxyphenyl)-1H-pyrazol-3-yl,-   5-(2-naphthyl)-1H-pyrazol-3-yl,-   5-(1-phenylpyrazol-3-yl)-1H-pyrazol-3-yl,-   5-(2-phenylpyridin-4-yl)-1H-pyrazol-3-yl,-   5-(2-phenylpyrimidin-4-yl)-1H-pyrazol-3-yl,-   5-[2-(2-fluorophenyl)pyrimidin-4-yl]-1H-pyrazol-3-yl,-   5-[2-(4-fluorophenyl)pyrimidin-4-yl]-1H-pyrazol-3-yl,-   5-(6-phenylpyrazin-2-yl)-1H-pyrazol-3-yl,-   5-(2-quinolyl)-1H-pyrazol-3-yl,-   5-(3-quinolyl)-1H-pyrazol-3-yl,-   5-(3-isoquinolyl)-1H-pyrazol-3-yl,-   5-(3-biphenylyl)-1H-pyrazol-3-yl,-   5-(3-trifluoromethylphenyl)-1H-1,2,4-triazol-3-yl,-   5-(2-naphthyl)-1H-1,2,4-triazol-3-yl,-   5-(3-biphenylyl)-1H-1,2,4-triazol-3-yl,-   6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(2-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(3-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   6-(4-fluorophenyl)-1H-pyrazolo[2,3-b][1,2,4]triazol-2-yl,-   2-phenyl-2,4-dihydroimidazo[4,5-d][1,2,3]triazol-5-yl,-   2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazol-5-yl,and the like.

X is nitrogen atom or methine.

T, U, V and W are independently methine or nitrogen atom, said methinebeing optionally substituted by a substituent selected from the groupconsisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, loweralkoxy and halo-lower alkoxy, and at least two of T, U, V and W are saidmethine groups.

“Methine which is optionally substituted by a substituent selected fromthe group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy,lower alkoxy and halo-lower alkoxy” refers to an unsubstituted methinegroup or a methine group having a substituent selected from the groupconsisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, loweralkoxy and halo-lower alkoxy.

Halogen as said substituent preferably includes, for example, fluorine,chlorine and the like.

Lower alkyl as said substituent preferably includes, for example,methyl, ethyl and the like.

Halo-lower alkyl as said substituent preferably includes, for example,difluoromethyl, trifluoromethyl and the like.

Lower alkoxy as said substituent preferably includes, for example,methoxy, ethoxy and the like.

Halo-lower alkoxy as said substituent preferably includes, for example,fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.

Said substituent includes, for example, halogen, lower alkyl, hydroxy,lower alkoxy and the like, and preferably halogen and the like.

The preferred embodiment of T, U, V and W includes the case where T, U,V and W are independently a methine group optionally having asubstituent selected from halogen, lower alkyl, hydroxy, and loweralkoxy, and preferably halogen, or more preferably the case where theyare an unsubstituted methine group; or the case where at least one of T,U, V and W is nitrogen.

Further, in the formula (I), a group represented by the formula (c):

(wherein T, U, V, W and X have each the same meaning as defined above)includes, for example, groups represented by the following formula (c₁):

(wherein X has the same meaning as defined above), preferably groupsrepresented by the following formula (C₂):

and the like.

The compounds of the present invention may include stereoisomers such asoptical isomers, diastereoisomers and geometrical isomers, or tautomersdepending upon the mode of substituents. The compounds of the presentinvention include all the stereoisomers, tautomers and their mixtures.

For example, compounds of the formula (I) wherein X is methine includestereoisomers such as a trans-form compound of the formula (I-1):

(wherein Az, T, U, V and W have each the same meaning as defined above)and a cis-form compound of the formula (I-2):

(wherein Az, T. U, V and W have each the same meaning as defined above),and trans-form compounds are preferable.

Also included within the scope of the invention are polymorphs, hydratesand solvates of the compounds of the present invention.

The present invention also includes prodrugs of the compounds of thisinvention within its scope. In general, such prodrugs are functionalderivatives of the compounds of the present invention which can bereadily converted in vivo into the required compound. Thus, in thetreatment methods for various diseases according to the presentinvention, the term “administering” shall encompass not onlyadministration of the compound specified in this disclosure but alsoadministration of a compound which is converted in vivo into thespecified compound when administered to a patient. Conventionalprocedures for selection and preparation of suitable prodrug derivativesare described, for example, in “Design of Prodrugs,” ed. H. Bundgaard,Elsevier (1985), which are entirely incorporated by reference in thisspecification. Metabolites of these compounds include active compoundsproduced upon introduction of compounds of the present invention intothe biological milieu, and are encompassed in the scope of the presentinvention.

Specific compounds of the formula (I) preferably include, for example,

-   4-(2-naphthyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazole,-   4-(4-bromophenyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazole,-   2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-4-(3-trifluoromethylphenyl)-1H-imidazole,-   4-(4-biphenylyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazole,-   4-(3-biphenylyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazole,-   2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-4,5-diphenyl-1H-imidazole,-   4-(4-fluorophenyl)-5-(3-pyridyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazole,-   4-methyl-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-phenyl-1H-imidazole,-   4-(3-methoxyphenyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazole,-   trans-4-(2-naphthyl)-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-1H-imidazole,-   trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-4-(3-trifluoromethylphenyl)-1H-imidazole,-   trans-2-(2-naphthyl)-4-[3-oxospiro[6-azaisobenzofuran-1(3H),l-cyclohexan]-4′-yl]-1H-imidazole,-   3-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(3-trifluoromethylphenyl)-1H-pyrazole,-   3-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyridin-4-yl)-1H-pyrazole,-   3-(3-biphenylyl)-5-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-pyrazole,-   3-(3-bromophenyl)-5-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-pyrazole,-   3-(3-biphenylyl)-5-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-pyrazole,-   3-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyridine-4-yl)-1H-pyrazole,-   3-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,-   trans-3-(3-biphenylyl)-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran-4-yl]-1H-pyrazole,-   trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(2-phenylpyridin-4-yl)-1H-pyrazole,-   trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(1-phenylpyrazol-3-yl)-1H-pyrazole,-   trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,-   trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(6-phenylpyrazin-2-yl)-1H-pyrazole,-   trans-3-(3-chlorophenyl)-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-1H-pyrazole,-   trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(2-quinolyl)-1H-pyrazole,-   trans-3-(3-biphenylyl)-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole,-   trans-3-(3-biphenylyl)-5-[3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole,-   trans-3-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,-   3-(2-naphthyl)-5-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin-1′-yl]-1H-1,2,4-triazole,-   3-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(3-trifluorometylphenyl)-1H-1,2,4-triazole,-   trans-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,-   cis-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,-   trans-6-(3-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,-   cis-6-(3-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,-   trans-6-(2-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,-   trans-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole,-   trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole,-   cis-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole,-   trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-phenyl-1H-imidazo    [1,2-b][1,2,4]triazole,-   trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-phenyl-1H-[1,2,4]triazolo    [2,3-b][1,2,4]triazole,-   trans-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2-phenyl-2,4-dihydroimidazo[4,5-d][1,2,3]triazole,-   trans-2-(2-fluorophenyl)-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2,4-dihydroimidazo[4,5-d][1,2,3]triazole,-   trans-2-(4-fluorophenyl)-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2,4-dihydroimidazo[4,5-d][1,2,3]triazole,-   trans-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazole,-   trans-6-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenyl-1H-imidazo[1,2-b]pyrazole,-   3-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin-1′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,-   3-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin-1′-yl]-5-[2-(2-fluorophenyl)pyrimidin-4-yl]-1H-pyrazole,    or-   3-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-[2-(4-fluorophenyl)pyrimidin-4-yl]-1H-pyrazole.

Among those compounds, preferred are

-   4-(2-naphthyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazole,-   3-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyridin-4-yl)-1H-pyrazole,-   3-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,-   trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,-   trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(6-phenylpyrazin-2-yl)-1H-pyrazole,-   trans-3-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,-   3-(2-naphthyl)-5-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-1,2,4-triazole,-   trans-6-(2-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,-   trans-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole,-   trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole,-   3-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin-1′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,-   3-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin-1′-yl]-5-[2-(2-fluorophenyl)pyrimidin-4-yl)-1H-pyrazole,-   3-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-[2-(4-fluorophenyl)pyrimidin-4-yl]-1H-pyrazole,    and the like.

The process for producing compounds of the present invention isillustrated as follows.

Compounds (I) of the present invention can be prepared, for example, bythe following Production Processes or the processes shown in Examples,but these embodiments are not intended to restrict the process forproducing compounds (I) of this invention.

Production Process 1

A compound of the formula (I-1):

(wherein Z is hydrogen atom, halogen, cyano, lower alkyl, halo-loweralkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl,lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² or -Q¹-Ar¹; andAr¹, Q¹, R¹, R², T. U, V, W. X and Y have the same meaning as definedabove), can be prepared by reacting a compound of the formula (II):

(wherein L¹ is a leaving group;

y and z are independently hydrogen atom, halogen, cyano, lower alkyl,halo-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl,lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R^(1P))R^(2P),-Q^(1P)-Ar^(1P) or optionally protected hydroxy;

Ar^(1P) is aryl or heteroaryl, any of which is optionally substituted bya substituent selected from the group consisting of halogen, nitro,lower alkyl, halo-lower alkyl, cyclo-lower alkyl, lower alkenyl, loweralkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, loweralkanoyl, lower alkoxycarbonyl, lower alkanoylamino, -Q^(2P)-Ar^(2P),optionally protected oxo, optionally protected hydroxy, optionallyprotected hydroxy-lower alkyl and optionally protected carboxyl;

Ar^(2P) is aryl or heteroaryl, any of which is optionally substituted bya substituent selected from the group consisting of halogen, cyano,lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, di-loweralkylamino, lower alkanoyl, aryl, optionally protected hydroxy-loweralkyl, optionally protected hydroxy and optionally protected loweralkylamino;

Q^(1P) and Q^(2P) are independently a single bond, oxygen atom,optionally protected carbonyl or —N(R³)—;

R^(1P) and R^(2P) are independently an amino-protecting group, animino-protecting group, hydrogen atom or lower alkyl, or R^(1p) andR^(2p), taken together, form lower alkylene which may be interrupted byoxygen atom, sulfur atom or optionally protected imino; and

R³ is hydrogen atom or lower alkyl) with a compound of the formula(III):

(wherein t, u, v and w are independently methine or nitrogen atom, saidmethine being optionally substituted by a substituent selected from thegroup consisting of halogen, lower alkyl, halo-loweralkyl, loweralkoxy,halo-loweralkoxy and optionally protected hydroxy, and at least two oft, u, v and w are said methine groups; and

X is nitrogen atom or methine) or its salt to give a compound of theformula (IV):

(wherein t, u, v, w, X, y and z have each the same meaning as definedabove), and optionally removing the protecting group(s) therefrom.

The present process refers to a process for preparing a compound of theformula (I) wherein Az is an optionally substituted 2-imidazolyl group,namely a compound of the formula (I-1).

The leaving groups represented by L¹ include, for example, halogen (e.g. chlorine, bromine, iodine), organic sulfonyl (e. g. methanesulfonyl,ethanesulfonyl, benzenesulfonyl), organic sulfonyloxy (e.g.methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy)and the like.

In the above reaction, when a reactant has an amino, imino, hydroxy,carboxyl, oxo, carbonyl or the like which does not participate in thereaction, the reaction may be carried out after protecting the amino,imino, hydroxy, carboxyl, oxo, or carbonyl with an amino- orimino-protecting group, a hydroxy-protecting group, acarboxyl-protecting group, an oxo-protecting group or acarbonyl-protecting group, followed by deprotection after completion ofthe reaction.

The “amino- or imino-protecting group” is not particularly restricted,so long as it has such protective function. There are employed, forexample, aralkyl (e.g. benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, benzhydryl, trityl);loweralkanoyl(e.g.formyl, acetyl, propionyl, butyryl, pivaloyl); benzoyl; arylalkanoyl(e.g. phenylacetyl, phenoxyacetyl); lower alkoxycarbonyl(e.g.methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl,tert-butoxycarbonyl); aralkyloxycarbonyl (e.g. benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl); lower alkylsilyl (e.g.trimethylsilyl, tert-butyldimethylsilyl); tetrahydropyranyl;trimethylsilylethoxymethyl; lower alkylsulfonyl (e.g. methylsulfonyl,ethylsulfonyl); arylsulfonyl (e.g. benzenesulfonyl, toluenesulfonyl) andthe like, among which particularly preferred are acetyl, benzoyl,tert-butoxycarbonyl, trimethylsilylethoxymethyl, methylsulfonyl and thelike.

The “hydroxy-protecting group” is not particularly restricted, so longas it has such protective function for hydroxy groups. There areemployed, for example, lower alkyl (e.g. methyl, ethyl, propyl,isopropyl, tert-butyl); lower alkylsilyl (e.g. trimethylsilyl,tert-butyldimethylsilyl); lower alkoxymethyl (e.g. methoxymethyl,2-methoxyethoxymethyl); tetrahydropyranyl; trimethylsilylethoxymethyl;aralkyl (e.g. benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, trityl); and acyl (e.g. formyl, acetyl),among which particularly preferred are methyl, methoxymethyl,tetrahydropyranyl, trityl, trimethylsilylethoxymethyl,tert-butyldimethylsilyl, acetyl and the like.

The “carboxyl-protecting group” is not particularly restricted, so longas it has such protective function for carboxyl groups. There areemployed, for example, lower alkyl (e.g. methyl, ethyl, propyl,isopropyl, tert-butyl); halo-lower alkyl (e.g. 2,2,2-trichloroethyl);lower alkenyl (e.g. 2-propenyl); aralkyl (e.g. benzyl, p-methoxybenzyl,p-nitrobenzyl, benzhydryl, trityl) and the like, among whichparticularly preferred are methyl, ethyl, tert-butyl, 2-propenyl,benzyl, p-methoxybenzyl, benzhydryl and the like.

The “oxo- or carbonyl-protecting group” is not particularly limited, solong as it has such protective function for oxo or carbonyl groups.There are employed, for example, acetals or ketals, such as ethyleneketal, trimethylene ketal, and dimethyl ketal and the like.

The reaction between a compound of the formula (II) and a compound ofthe formula (III) is usually carried out by employing 0.5 moles toexcessive moles, preferably an equivalent to 1.5 moles, of compound(III) relative to 1 mole of compound (II).

The reaction is usually carried out in an inert solvent. Preferableexamples of such solvent are methylene chloride, chloroform,tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone,dimethyl sulfoxide and the like, or a mixture thereof and the like.

The reaction is preferably carried out in the presence of a base such asorganic bases (e.g. triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine), inorganic bases (e.g. sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,sodium hydroxide, potassium hydroxide) and the like.

The base is used in equimolar amount or in excess moles, preferably 1 to5 moles, relative to 1 mole of the compound of the formula (II).

The reaction temperature is usually from 0° C. to 200° C., preferably20° C. to 150° C.

The reaction time is usually 5 minutes to 7 days, preferably 30 minutesto 24 hours.

A usual treatment is carried out after completion of the reaction toobtain a crude product of a compound of the formula (IV). The resultingcompound of the formula (IV) is, with or without purification accordingto the common method, subjected to optional removal of the protectinggroup for the amino, hydroxy, carboxyl, oxo, carbonyl or the like,thereby to produce a compound of the formula (I-1).

Although the method for the removal of said protecting groups dependsupon the kind of the protecting groups, the stability of a desiredcompound (I-1) and the like, it is carried out by, for example, asolvolys is using an acid or a base, that is, a method wherein forexample 0.01 mole to a large excess of acid, preferably trifluoroaceticacid, formic acid, hydrochloric acid and the like, or an equivalent moleto a large excess of base, preferably potassium hydroxide, calciumhydroxide and the like is acted; a chemical reduction using a metalhydride complex; or a catalytic reduction using a palladium-carboncatalyst, a Raney-nickel catalyst, etc.; and the like, according to, forexample, a method described in the literature (Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons, (1981)) or itssimilar method.

Production Process 2

A compound of the formula (I-2):

(wherein T, U, V, W, X, Y and Z are the same meaning as defined above),can be prepared by reacting a compound of the formula (V):

(wherein y is the same meaning as defined above) or its salt, with acompound of the formula (VI):

(wherein L¹, t, u, v, w, X and z are the same meaning as defined above)or its salt to give a compound of the formula (VII):

(wherein t, u, v, w, X, y and z have each the same meaning as definedabove), and optionally removing the protecting group(s) therefrom.

The present process refers to a process for preparing a compound of theformula (I) wherein Az is an optionally substituted 4-imidazolyl group,namely a compound of the formula (I-2).

The reaction between a compound of the formula (V) and a compound of theformula (VI) is usually carried out by employing 0.5 moles to excessivemoles, preferably 1 to 1.5 moles of the compound (VI), relative to 1mole of a compound of the formula (V).

The reaction is usually carried out in an inert solvent. Preferableexamples of such solvent are methylene chloride, chloroform,tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone,dimethyl sulfoxide, and a mixture thereof and the like.

The reaction is preferably carried out in the presence of a base such asorganic bases (e.g. triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine), inorganic bases (e.g. sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,sodium hydroxide, potassium hydroxide) and the like.

The base is used in equimolar amount or in excess moles, preferably 1 to5 moles, relative to 1 mole of the compound of the formula (VI).

The reaction temperature is usually from 0° C. to 200° C., preferably20° C. to 150° C.

The reaction time is usually 5 minutes to 7 days, preferably 5 minutesto 24 hours.

A compound of the formula (I-2) can be produced by treating a reactionmixture in the usual way after removal of the said protecting group(s)when the product has a protecting group after completion of thereaction, or by treating the mixture directly in the usual way when theprotecting group is absent.

The deprotection and post-treatment may be carried out according to amethod similar to the method described in Production Process 1.

Production Process 3

A compound of the formula (I-3):

(wherein T, U, V, W, X, Y and Z are the same meaning as defined above),can be prepared by subjecting a compound of the formula (VIII):

(wherein t, u, v, w, X, y and z are the same meaning as defined above)and hydrazine to dehydrative ring closure to give a compound of theformula (IX):

(wherein t, u, v, w, X, y and z have each the same meaning as definedabove), and optionally removing the protective group(s) therefrom.

The present process refers to a process for preparing a compound of theformula (I) wherein Az is an optionally substituted 3-pyrazolyl group,namely a compound of the formula (I-3).

The reaction between a compound of the formula (VIII) and hydrazine isusually carried out by employing 0.5 to excess moles, preferably 1.0 to1.5 moles of hydrazine, relative to 1 mole of a compound of the formula(VIII).

The reaction is usually carried out in the presence of an inert solvent.Preferred examples of the inert solvent are ethanol, propanol, butanol,pentanol, 1,4-dioxane, dimethoxyethane, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, and a mixture thereof and the like.

The reaction temperature is usually from 0° C. to 200° C., preferably20° C. to 150° C.

The reaction time is usually from 5 minutes to 7 days, preferably from30 minutes to 24 hours.

A compound of the formula (I-3) can be produced by optionallydeprotecting the protecting group(s) for the amino, hydroxyl, carboxyl,oxo and carbonyl groups from the resulting compound of the formula (IX)in the usual way using appropriate combination of deprotection methodswith or without purification.

The removal of the protecting group(s), and the post-treatment may beconducted according to a method similar to the method described in theabove Production Process 1.

Production Process 4

A compound of the formula (I-4):

(wherein T, U, V, W, X and Y are the same meaning as defined above), canbe prepared by reacting a compound of the formula (X):

(wherein y is the same meaning as defined above) or its salt, with acompound of the formula (XI):

(wherein t, u, v, w and X are the same meaning as defined above), or itssalt to give a compound of the formula (XII):

(wherein t, u, v, w, X and y have each the same meaning as definedabove), and optionally removing the protecting group(s) therefrom.

The present process refers to a process for preparing a compound of theformula (I) wherein Az is an optionally substituted 1, 2,4-triazol-3-ylgroup, namely a compound of the formula (I-4).

The reaction between a compound of the formula (X) and a compound of theformula (XI) is usually carried out by employing 0.5 to 5 moles,preferably 0.7 to 3 moles of the compound (XI), relative to 1 mole ofthe compound (X)

The reaction is usually carried out in the absence or presence of aninert solvent. Preferred examples of the inert solvent are benzene,toluene, xylene, methylene chloride, chloroform, hexane, and a mixturethereof and the like.

The reaction temperature is usually from −20° C. to the boiling point ofthe solvent used, preferably 20° C. to 200° C.

The reaction time is usually from 30 minutes to 7 days, preferably from3 hours to 3 days.

It is preferred to perform the above reaction in the presence of a Lewisacid. As the Lewis acid, there are exemplified by zinc dichloride,titanium tetrachloride, scandium trifluoromethanesulfonate, yttriumtrifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, and thelike.

The amount of the Lewis acid to be used is usually 10 to 200 mole %,preferably 20 to 100 mole %, relative to 1 mole of a compound of theformula (X).

When the reaction is carried out in the presence of a Lewis acid, it maybe conducted without any solvent or preferably in the presence of asolvent such as methylene chloride, chloroform, benzene, toluene,xylene, and a mixture thereof.

The reaction temperature is usually from 0° C. to the boiling point ofthe solvent used, preferably room temperature to 150° C.

The reaction time is usually from 1 hour to 7 days, preferably from 12hours to 3 days.

A compound of the formula (I-4) can be produced by treating a reactionmixture in the usual way after removal of the said protecting group(s)when the product has a protecting group after completion of thereaction, or by treating the mixture directly in the usual way when theprotecting group is absent.

The removal of the protecting group(s), and the post-treatment may beconducted according to a method similar to the method described in theabove Production Process 1.

Production Process 5

A compound of the formula (I-5):

(wherein Az¹ is a group comprising a monocyclic azole having bondsattached respectively to the adjacent ring atoms, said monocyclic azolebeing optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy,lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, loweralkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹; and

Ar¹, Q¹, R¹, R², T, U, V and W are the same meaning as defined above),can be prepared by reacting a compound of the formula (XIII):

(wherein Az^(1P) is a group comprising a monocyclic azole having bondsattached respectively to the adjacent ring atoms, said monocyclic azolebeing optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl,lower alkylsulfonyloxy, —N(R^(1P))R^(2P), -Q^(1P)-Ar^(1P), andoptionally protected hydroxy; and

Ar^(1P), Q^(1P), R^(1P) and R^(2P) are the same meaning as definedabove) or its salt with a compound of the formula (XIV)

(wherein t, u, v and w are the same meaning as defined above) or itssalt or reactive derivative to give a compound of the formula (XV):

(wherein Az^(1P), t, u, v and w have each the same meaning as definedabove), followed by subjecting the compound (XV) to intramoleculardehydrative ring closure to give a compound of the formula (XVI):

(wherein Az^(1P), t, u, v and w have each the same meaning as definedabove), and optionally removing the protecting group(s).

The present process refers to a process for preparing a compound of theformula (I) wherein Az is an optionally substituted bicyclic aromaticring wherein the same or different azoles are fused, and X is methine,namely a compound of the formula (I-5).

The reaction between a compound of the formula (XIII) and a compound ofthe formula (XIV) is usually carried out by employing 0.5 to 5 moles,preferably 0.7 to 3 moles of the compound (XIV), relative to 1 mole ofthe compound (XIII).

The reaction is usually carried out in an inert solvent. Preferredexamples of the inert solvent are methylene chloride, chloroform,tetrahydrofuran, dimethylformamide, pyridine, and a mixture thereof.

The above reaction is preferably carried out in the presence of acondensing agent including, for example, N,N′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,benzotriazol-1-yloxy-tris-(dimethylamino)phosphoniumhexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidino-phosphoniumhexafluorophosphate, bromotris(dimethylamino)phosphoniumhexafluorophosphate, diphenylphosphoric azide, 1,1′-carbonyldiimidazoleand the like.

Such condensing agent can be usually used in 1 to excess moles,preferably 1 to 1.5 moles, relative to 1 mole of a compound of theformula (XIV).

The reaction temperature is usually from −50° C. to 100° C., preferably−20° C. to 50° C.

The reaction time is usually from 30 minutes to 7 days, preferably from1 to 24 hours.

In place of the carboxylic acid of the formula (XIV), a reactivederivative of said carboxylic acid may be reacted with a compound of theformula (XIII), thereby to produce a compound of the formula (XV) can beprepared.

Examples of such activated derivatives of the carboxylic acid of theformula (XIV) are acid halides, mixed anhydrides, active esters, activeamides and the like.

The acid halides of the carboxylic acid of the formula (XIV) can beprepared by reacting a carboxylic acid of the formula (XIV) with ahalogenating agent in a conventional manner. The halogenating agent usedincludes, for example, thionyl chloride, phosphorus trichloride,phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide,oxalyl chloride, phosgene and the like.

The mixed anhydrides of the carboxylic acid of the formula (XIV) can beprepared by reacting a carboxylic acid of the formula (XIV) with analkyl chlorocarbonate (e.g. ethyl chlorocarbonate), an aliphaticcarboxylic acid chloride (e.g. pivaloyl chloride) and the like accordingto the conventional method.

The active esters of the carboxylic acid of the formula (XIV) can beprepared by reacting a carboxylic acid of the formula (XIV) with anN-hydroxy compound (e.g. N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxybenzotriazole); a phenol compound (e.g. 4-nitrophenol,2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol) and thelike in the presence of a condensing agent (e.g.N,N′-dicyclohexyl-carbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) according to theconventional method.

The active amides of the carboxylic acid of the formula (XIV) can beprepared by reacting a carboxylic acid of the formula (XIV) with1,1′-carbonyldiimidazole, 1,1′-carbonylbis (2-methyl-imidazole) and thelike according to the conventional method.

The reaction between a compound of the formula (XIII) and a reactivederivative of the carboxylic acid of the formula (XIV) is usuallycarried out by employing 0.5 moles to excess moles, preferably 1 to 1.5moles of the reactive derivative of the carboxylic acid (XIV), relativeto 1 mole of compound (XIII).

The reaction is usually carried out in an inert solvent. Preferableexamples of such inert solvent are methylene chloride, chloroform,tetrahydrofuran, dimethylformamide, pyridine, and a mixture thereof andthe like.

The above reaction may proceed in the absence of a base, but it ispreferable to carry out the reaction in the presence of a base topromote the reaction smoothly.

The bases include organic bases (e.g. triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine), or inorganicbases (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogen carbonate).

It is preferable to employ 1 to excessive moles of said base to 1 moleof a compound of the formula (XIII). When the base is liquid, such basecan also be used as a solvent.

The reaction temperature is usually −50° C. to 100° C. preferably −20°C. to 50° C.

The reaction time is usually 5 minutes to 7 days, preferably 30 minutesto 24 hours.

A usual treatment is carried out after completion of the reaction toobtain a crude product of a compound of formula (XV). The resultingcompound of the formula (XV) may be, with or without purificationaccording to the conventional manner, subjected to optionalintramolecular ring closure condensation.

The intramolecular ring closure condensation for preparing a compound ofthe formula (XVI) from the compound (XV) is usually carried out in thepresence of an inert solvent or without any solvent.

Preferred examples of such inert solvents are ethanol, propanol,butanol, pentanol, 1,4-dioxane, dimethoxyethane, dimethylformamide,dimethyl sulfoxide, benzene, toluene, xylene, and a mixture thereof andthe like.

The reaction temperature is usually from room temperature to the boilingpoint of the solvent used, preferably 80° C. to 190° C.

The reaction time is usually from 5 hours to 7 days, preferably from 12hours to 3 days.

The above ring closure may be carried out in the presence of adehydrating agent or a catalytic amount of Lewis acid. The dehydratingagent includes, for example, cesium fluoride, phosphorus oxychloride,phosphorus pentachloride, polyphosphoric acid, thionyl chloride and thelike. As the Lewis acid, there are exemplified by scandiumtrifluoromethanesulfonate, yttrium trifluoromethanesulfonate, lanthanumtrifluoromethanesulfonate, lanthanide trifluoromethanesulfonate and thelike. The ring closure is carried out preferably without any solvent, orin the presence of a solvent such as methylene chloride, chloroform,benzene, toluene, xylene and the like or a mixture thereof.

The amount of the dehydrating agent to be used is usually 1 mole toexcessive moles, preferably 2 to 10 moles, relative to 1 mole of acompound of the formula(XV), and that of the Lewis acid is 10 to 50 mole%, preferably 10 to 30 mole %.

In general, the reaction temperature is preferably from room temperatureto the boiling point of the solvent used.

The reaction time is from 1 hour to 7 days, preferably from 5 hours to 3days.

A compound of the formula (I-5) can be produced by treating the reactionmixture in the usual way after removal of the said protecting group(s)when the product has a protecting group after completion of thereaction, or by treating the mixture directly in the usual way when theprotecting group is absent.

The removal of the protecting group(s), and the post-treatment may beconducted according to a method similar to the method described in theabove Production Process 1.

Production Process 6

A compound of the formula (I-6):

(wherein T, U, V, W, X, Y and Z are the same meaning as defined above),can be prepared by reacting a compound of the formula (II):

(wherein L¹, y and z are the same meaning as defined above), with acompound of the formula (XVII):

(wherein t, u, v, w and X are the same meaning as defined above) or itssalt to give a compound of the formula (XVIII):

(wherein t, u, v, w, X, y and z have each the same meaning as definedabove), followed by subjecting the compound of the formula (XVIII) tointramolecular dehydrative ring closure to give a compound of theformula (XIX):

(wherein t, u, v, w, X, y and z have each the same meaning as definedabove), and optionally removing the protecting group(s).

The present process refers to a process for preparing a compound of theformula (I) wherein Az is an optionally substituted5H-imidazo[1,2-b]pyrazol-6-yl group, namely a compound of the formula(I-6).

The reaction between a compound of the formula (II) and a compound ofthe formula (XVII) is usually carried out by employing 0.5 moles toexcessive moles, preferably 0.5 to 1.5 moles of the compound (XVII),relative to 1 mole of the compound (II).

The reaction is usually carried out in an inert solvent. Preferredexamples of such inert solvent are methylene chloride, chloroform,tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone,dimethyl sulfoxide, and a mixture thereof and the like.

The above reaction may be carried out preferably in the presence of abase. The bases used include organic bases (e.g. triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine), or inorganicbases (e.g. sodium hydrogen carbonate, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide).

The amount of the base to be used is usually equivalent mole toexcessive moles, preferably 1 to 5 moles, of a compound of the formula(II).

The reaction temperature is usually 0° C. to 200° C. preferably 20° C.to 150° C.

The reaction time is usually 5 minutes to 7 days, preferably 30 minutesto 24 hours.

A usual treatment is carried out after completion of the reaction toobtain a crude product of a compound of the formula (XVIII). Theresulting compound of the formula (XVIII) may be subjected, with orwithout purification according to the conventional manner, to optionalintramolecular ring closure condensation.

The intramolecular ring closure condensation for preparing a compound ofthe formula (XIX) from the compound (XVIII) is usually carried out inthe presence of an inert solvent or without any solvent.

Preferred examples of such inert solvents are ethanol, propanol,butanol, pentanol, 1,4-dioxane, dimethoxyethane, dimethylformamide,dimethyl sulfoxide, benzene, toluene, xylene, and a mixture thereof andthe like.

The reaction temperature is usually from room temperature to the boilingpoint of the solvent used, preferably 80° C. to 190° C.

The reaction time is usually from 5 hours to 7 days, preferably from 12hours to 3 days.

The above ring closure may be carried out in the presence of adehydrating agent or a catalytic amount of Lewis acid. The dehydratingagent includes, for example, cesium fluoride, phosphorus oxychloride,phosphorus pentachloride, polyphosphoric acid, thionyl chloride and thelike. As the Lewis acid, there are exemplified by scandiumtrifluoromethanesulfonate, yttrium trifluoromethanesulfonate, lanthanumtrifluoromethanesulfonate, lanthanide trifluoromethanesulfonate and thelike. The ring closure is carried out preferably without any solvent, orin the presence of a solvent such as methylene chloride, chloroform,benzene, toluene, xylene and the like or a mixture thereof.

The amount of the dehydrating agent to be used is usually 1 mole toexcessive moles, preferably 2 to 10 moles, relative to 1 mole of acompound of the formula(XVIII), and that of the Lewis acid is 10 to 50mole %, preferably 10 to 30 mole %.

In general, the reaction temperature is preferably from room temperatureto the boiling point of the solvent used.

The reaction time is from 1 hour to 7 days, preferably from 5 hours to 3days.

A compound of the formula (I-6) can be produced by treating the reactionmixture in the usual way after removal of the said protecting group(s)when the product has a protecting group after completion of thereaction, or by treating the mixture directly in the usual way when theprotecting group is absent.

The removal of the protecting group(s), and the post-treatment may beconducted according to a method similar to the method described in theabove Production Process 1.

The compounds of the formula (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6)may be readily isolated and purified by the conventional separationtechnique, and examples of such technique are solvent extraction,recrystallization, column chromatography, preparative thin layerchromatography and the like.

These compounds may be converted into the pharmaceutically acceptablesalts or esters by the conventional method, and on the contrary, theconversion of the salts or esters into free compounds may also becarried out according to the conventional method.

The compounds of the formulae (II), (III), (V), (VI), (VIII), (X), (XI),(XIII), (XIV) and (XVII) are commercially available, or can be preparedaccording to the common methods or analogous methods thereto, or themethods shown in Examples and Reference Examples, optionally employed incombination.

Although there is no particular limitation to “salts” of compounds ofthe formulae (III), (V), (VI), (X), (XI), (XIII), (XIV) and (XVII) solong as they do not affect the reaction, such salts include the commonsalts, for example, base addition salt to the carboxyl group when thecompound has a carboxyl group, or acid addition salt to the amino orbasic heterocyclic group when the compound has amino or basicheterocyclic group(s), and the like.

Aforesaid base addition salts include salts with alkali metals (forexample sodium, potassium); alkaline earth metals (for example calcium,magnesium); ammonium or organic amines (for example trimethylamine,triethylamine, dicyclohexylamine, ethanolamine, diethanolamine,triethanolamine, procaine, N,N′-dibenzylethylenediamine), and the like.

Aforesaid acid addition salts include inorganic acid salts (for examplehydrochloride, sulfate, nitrate, phosphate, perchlorate), organic acidsalts (for examplemaleate, fumarate, tartarate, citrate, ascorbate,trifluoroacetate), sulfonates (for example methanesulfonate,isethionate, benzenesulfonate, p-toluenesulfonate), and the like.

The utility of compounds of the present invention as a medicament isproved by the following pharmacological tests.

Pharmacological Test 1 (NPY Binding Inhibition Test)

cDNA sequence encoding human NPY Y5 receptor (cf. International patentpublication number WO96/16542) was cloned intoexpressionvectors pcDNA3,pRc/RSV (made by Invitrogen Inc.) and pCI-neo (made by Promega Inc.).The expression vectors thus obtained were transfected to host cellsCOS-7, CHO and LM (tk-) (American Type Culture Collection) by cationiclipid method (Proceedings of the National Academy of Sciences of theUnited States of America, 84: 7413 (1987)) to give NPY Y5 receptorexpression cells.

A membrane sample prepared from the cells which expressed NPY Y5receptor was incubated together with a test compound and [¹²⁵I]peptideYY (made by NEN) (20,000 cpm) in an assay buffer (25 mM Tris buffer, pH7.4, containing 10 mM magnesium chloride, 1 mM phenylmethylsulfonylfluoride, 0.1% bacitracin and 0.5% bovine serum albumin) at 25° C. for 2hours, then filtered through a glass filter GF/C and washed with 5 mMTris buffer (pH7.4) containing 0.3% BSA. The radioactivity of the cakeon the glass filter was measured. Non-specific binding was measured inthe presence of 1 μM peptide YY, and a 50% Inhibitory Concentration(IC₅₀) of the test compound against specific peptide YY binding wasdetermined (Endocrinology, 131: 2090 (1992)). The results are shown inTable 1.

TABLE 1 Compounds IC50(nM) Example 1 1.7 Example 14 1.7 Example 19 1.6Example 23 2.7 Example 24 3.9 Example 29 3.9 Example 30 4.2 Example 343.5 Example 35 3.3 Example 36 1.8 Example 45 1.5 Example 46 1.5 Example47 2.2

As shown above, the compounds of this invention potently inhibitedpeptide YY (NPY homologue) binding to NPY Y5 receptors.

Pharmacological Test 2 (Brain/Cerebrospinal Fluid Transport Test)

A test compound was orally or intravenously administered to male SD rats(7-10 weeks old, 200-400 g), and whole blood was collected from theabdominal aorta of said rats anesthetized with etherat predeterminedtime, using a heparin-treated syringe. Then, the head skin was cut open,and a dental 30G needle was inserted between the cervical vertebrae, andit was further inserted into the cavum subarachnoideale. After 50 to 100μL cerebrospinal fluid had been collected by a 1 ml-syringe through atube connected to said dental 30G needle, the brain was extracted. Theblood sample was centrifuged (4° C., 6,000 r.p.m., 10 minutes) tocollect the plasma, to which was added 3-fold amount of ethanolcontaining an internal standard, and the mixture was stirred. The brainsample was homogenized after addition of 2 ml water, an aliquot of thehomogenate was taken and 3-fold amount of ethanol containing an internalstandard was added thereto and stirred. The cerebrospinal fluid wasstirred after adding 3-fold amount of ethanol containing an internalstandard. The samples thus obtained were allowed to stand at −20° C. for20 minutes, and then centrifuged (4° C., 12,000 g, 10 minutes). Thesupernatant was analyzed by LC/MS/MS, and the concentration of the testcompound in the plasma, brain, and cerebrospinal fluid were measured bythe method using a relative calibration curve.

The results revealed that concentrations of the compound of Example 29in the brain, cerebrospinal fluid and plasma were 3.01 mmol/g, 0.015 μMand 1.62 μM respectively, 2 hours after oral administration (10 mg/kg).

The compounds of the formula (I) can be administered orally orparenterally and, by formulating into a suitable administrable form, maybe administered as an agent for treating or preventing various diseases,including, for example, cardiovascular disorders such as angina, acuteor congestive heart failure, myocardial infarction, hypertension,nephropathy, electrolyte abnormality, vasospasm, arteriosclerosis, etc.;central nervous system disorders such as bulimia, depression, anxiety,seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal,circadian rhythm disorders, schizophrenia, memory impairment, sleepdisorders, cognitive impairment, etc.; metabolic diseases such asobesity, diabetes, hormone abnormality, hypercholesterolemia,hyperlipidemia, gout, fatty liver, etc.; genital or reproductivedisorders such as infertility, preterm labor, sexual dysfunction, etc.;gastro-intestinal disorders; respiratory disorder; inflammatorydiseases; glaucoma; atherosclerosis; hypogonadism; hyperandrogenism;polycystic ovary syndrome; hirsutism; gastro-intestinal motilitydisorder; obesity-related gastro-esophageal reflux; obesityhypoventilation (Pickwickian syndrome); sleep apnea; inflammation;systemic inflammation of the vasculature; osteoarthritis; insulinresistance; bronchoconstriction; alcohol preference; metabolic syndrome(syndrome X); Alzheimer's disease; cardiac hypertrophy; left ventricularhypertrophy; hypertriglyceridemia; low HDL cholesterol; cardiovasculardisorders such as coronary heart disease (CHD), cerebrovascular disease,stroke, peripheral vascular disease, and sudden death; gallbladderdiseases; cancers (breast cancer, endometrial cancer, colon cancer);breathlessness; hyperuricemia; impaired fertility; low backpain;increased anesthetic risk; renal system diseases; renal abnormalitiessuch as dysfunction in body fluid flow, abnormalities of materialtransportation, and renal failure; shock; arrhythmia; symptoms relatedto surge in sympathomimetic activity during or after operation oncoronary artery or gastrointestinal tracts; diseases related to brain orcentral nervous system, such as cerebral infarction, neurodegeneration,cerebral stroke, cerebrovascular spasm or cerebral hemorrhage; symptomsrelated to pain or nociception; diseases related to abnormalities ingastrointestinal motility or secretion, such as various ileuses, urinaryincontinence, and Crohn's disease; eating disorders such as anorexia andbulimia; inflammatory symptoms or diseases; asthma; bronchioleconstriction; or diseases related to abnormal secretion of hormones suchas luteinizing hormone, growth hormone, insulin, and luteotropichormone.

In clinical use, the compounds of this invention may be administeredafter being formulated, together with pharmaceutically acceptableadditives, into an appropriate preparation according to the mode ofadministration. As for said additives, those which are usually used inthe field of pharmaceutical formulation may be used, for example,gelatin, lactose, sucrose, titaniumoxide, starch, crystallinecellulose,hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch,microcrystalline wax, white petrolatum, magnesium methasilicatealuminate, anhydrous calcium phosphate, citric acid, trisodium citrate,hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester,polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenatedcastor oil, polyvinyl pyrrolidone, magnesium stearate, light silicicanhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propyleneglycol, polyalkylene glycol, cyclodextrin or hydroxypropyl cyclodextrinand the like.

A mixture with said additives may be formulated into the form of solidpreparations (for example tablets, capsules, granules, powder,suppositories); or liquid preparations (for example syrups, elixirs,injections). Such preparations may be formulated according to thetechniques well known in the art of pharmaceutical formulation. Liquidpreparations may be in the form of preparations which are dissolved orsuspended in water or other appropriate media when used, and injectablepreparations in particular may be dissolved or suspended inphysiological saline or glucose solution if necessary, optionallytogether with a buffer and a preservative.

The compounds of the present invention are effective for humans ormammals other than humans in need of treatment or prevention ofdiseases. Mammals preferably include humans which may be male or female.As the mammal other than humans, there are exemplified by companionanimals such as dog, cat and the like. The compounds of the presentinvention are effective against obesity or diseases related to obesity.An ordinarily skilled physician, veterinarian or clinician can readilydetermine whether or not treatment with the compound of the presentinvention is required.

When compounds of this invention are used clinically, for example, adaily dose for an adult is 0.01-100 mg/kg, preferably 0.03-1 mg/kg withsimultaneous or divided administration when administered orally, and0.001-10 mg/kg, preferably 0.001-0.1 mg/kg, more preferably 0.01-0.1mg/kg with simultaneous or divided administration when administeredparenterally, though the dose and the frequency of dosage may varydepending upon the sex, age, body weight, the degree of symptoms and thekind and range of the desired treatment effects.

An ordinarily skilled physician, veterinarian or clinician can readilydetermine and prescribe the effective amount of the drug required toprevent, suppress or arrest the progress of diseases.

All the said preparations may contain 1.0 to 100 wt. %, preferably 1.0to 60 wt. % of compounds of this invention and may also contain othertherapeutically effective compounds.

The compounds of the present invention can be used in combination withother agents useful for treating metabolic disorders and/or eatingdisorders. The individual component of such combinations can beadministered separately at different times or concurrently in divided orsingle combination forms during the course of therapy. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or divided administration and the term “administering” isto be interpreted accordingly. The scope of combinations of thecompounds of this invention with other agents useful for treatingmetabolic disorders and/or eating disorders includes in principle anycombination of any pharmaceutical composition useful for treatingmetabolic disorders and/or eating disorders.

Diabetes is caused by multiple factors and is most simply characterizedby elevated levels of plasma glucose (hyperglycemia) in the fastingstate. There are two generally recognized forms of diabetes: type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), in whichpatients produce little or no insulin, the hormone which regulatesglucose utilization, and type 2 diabetes, or noninsulin-dependentdiabetes mellitus (NIDDM), wherein patients produce insulin and evenexhibit hyperinsulinemia (plasma insulin levels that are the same oreven elevated in comparison with non-diabetic subjects), while at thesame time demonstrating hyperglycemia. Type 1 diabetes is typicallytreated with exogenous insulin administered via injection. However, type2 diabetics often develop “insulin resistance”, such that the effect ofinsulin in stimulating glucose and lipid metabolism in the maininsulin-sensitive tissues, namely, muscle, liver and adipose tissues, isdiminished. Patients who are insulin resistant but not diabetic haveelevated insulin levels that compensate for their insulin resistance, sothat serum glucose levels are not elevated. In patients with NIDDM, theplasma insulin levels, even when they are elevated, are insufficient toovercome the pronounced insulin resistance, resulting in hyperglycemia.Thus, it is difficult to treat patients with NIDDM by singleadministration of foreign insulin.

Insulin resistance is primarily due to a receptor binding defect that isnot yet completely understood. Resistance to insulin results ininsufficient activation of glucose uptake, diminished oxidation ofglucose and storage of glycogen in muscle, inadequate insulin repressionof lipolysis in adipose tissue and inadequate glucose production andsecretion by the liver. The persistent or uncontrolled hyperglycemiathat occurs in diabetics is associated with increased morbidity andpremature mortality. Type 2 diabetics are at increased risk ofdeveloping cardiovascular complications, e.g., atherosclerosis, coronaryheart disease, stroke, peripheral vascular disease, hypertension,nephropathy, neuropathy and retinopathy.

Non-insulin dependent diabetes is also associated with cardiachypertrophy, in particular left ventricular hypertrophy (Devereux, R.B., Circulation, 101:2271-2276(2000)). Cardiac hypertrophy, such as leftventricular hypertrophy, is due to the response of the heart to chronicpressure or volume overload. Left ventricular hypertrophy (LVH) ischaracterized by thickening of the left ventricular wall, includingincreased left ventricular mass and increased left ventricular wallthickness, and is defined as a left ventricular mass index exceeding 131g/m² of the body surface area in men, and 100 g/m² in women (Savage etal., The Framingham Study, Circulation, 75 (1 Pt 2): 26-33 (1987).

Left ventricular hypertrophy is independently associated with increasedincidence of cardiovascular disease, such as congestive heart failure,ischaemic heart disease, cardiovascular and all-cause mortality, suddendeath, and stroke. Regression of left ventricular hypertrophy has beenassociated with a reduction in cardiovascular risk. It has also beenfound that the incidence of morbid events in patients with progressionof left ventricular hypertrophy is greater than in patients withregression of left ventricular hypertrophy.

Current treatments for hypertrophy include non-pharmacologicalinterventions, such as weight reduction, sodium restriction, and aerobicphysical exercise can reduce left ventricular mass (Ghali, J. K. et al.,American Journal of Geriatric Cardiology, 6:38-49 (1997).

Many patients who have insulin resistance but have not yet developedtype 2 diabetes are also at a risk of developing metabolic syndrome,also referred to as syndrome X, insulin resistance syndrome, orplurimetabolic syndrome. The period of 5 to 10 years preceding thedevelopment of impaired glucose tolerance is associated with a number ofhormonal imbalances, which give rise to an enlargement of visceral fatmass, hypertension, insulin resistance, and hyperlipidemia (Bjornstop,P., Current Topics in Diabetes Research, eds. Belfore, F., Bergman, R.N., and Molinath, G. M., Front Diabetes, Basel, Karger, 12:182-192(1993)). Similarly, metabolic syndrome is characterized by insulinresistance, along with abdominal obesity, hyperinsulinemia,hyperglycemia, syndrome X, low HDL and high VLDL. Although the causalrelationship between the various components of metabolic syndromeremains to be confirmed, insulin resistance appears to play an importantrole (Requen, G. M., et al., N. Eng. J. Med. 334:374-381(1996); Despres,J-P., et al., N. Engl. J. Med. 334:952-957 (1996); Wajchenberg, B. L.,et al., Diabetes/Metabolism Rev. 10:19-29 (1994)). Metabolic syndromepatients, whether or not they develop overt diabetes mellitus, are atincreased risk of developing the cardiovascular complications listedabove. Associations have also been found between left ventricularhypertrophy and metabolic syndrome (Marcus, R. et al. Circulation,90:928-936 (1994); Lind, L. etal., J Hypertens. 13:433-38(1995);Paolisso, G et al., Am J Hypertens., 10:1250-1256 (1997).

Diabetes is treated with a variety of therapeutic agents includinginsulin sensitizers, such as PPARγ agonists, such as glitazones;biguanides; protein tyrosine phosphatase-1B inhibitors; dipeptidylpeptidase IV inhibitors; insulin; insulin mimetics; sulfonylureas;meglitinides; α-glucoside hydrolase inhibitors; and α-amylaseinhibitors.

Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinides, whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinides becomeineffective, can result in insulin concentrations high enough tostimulate insulin-resistant tissues. However, dangerously low levels ofplasma glucose can result, and increasing insulin resistance due to theeven higher plasma insulin levels can occur. The biguanides increaseinsulin sensitivity resulting in some correction of hyperglycemia.Alpha-amylase inhibitors inhibit the enzymatic degradation of starch orglycogen into maltose, which also reduces the amounts of bioavailablesugars. Metformin monotherapy is often used for treating type 2 diabeticpatients who are also obese and/or dyslipidemic. Lack of appropriateresponse to metformin is often followed by treatment with sulfonylureas,thiazolidinediones, insulin, or alpha glucosidase inhibitors. However,the two biguanides, phenformin and metformin, can also induce lacticacidosis and nausea/diarrhea, respectively. Alpha glucosidaseinhibitors, such as acarbose, work by delaying absorption of glucose inthe intestine.

The glitazones, also known as thiazolidinediones (i.e.5-benzylthiazolidine-2,4-diones), are a more recently described class ofcompounds with potential for a novel mode of action in a melioratingmany symptoms of type 2 diabetes. These agents substantially increaseinsulin sensitivity in muscle, liver and adipose tissue in severalanimal models of type 2 diabetes resulting in partial or completecorrection of the elevated plasma levels of glucose without occurrenceof hypoglycemia. The glitazones that are currently marketed are agonistsof the peroxisome proliferator activated receptor (PPAR) gamma subtype.PPAR-gamma agonism is generally believed to be responsible for theimproved insulin sensitization that is observed with the glitazones.Newer PPAR agonists that are being developed for treatment of Type 2diabetes and/or dyslipidemia are agonists of one or more of the PPARalpha, gamma and delta subtypes.

However, treatment of diabetes with PPAR γ agonists has been associatedwith cardiac hypertrophy, or an increase in heart weight. Recentlabeling revisions for Avandia (rosiglitazone maleate), a PPARγ agonist,indicate that patients may experience fluid accumulation andvolume-related events such as edema and congestive heart failure.Cardiac hypertrophy related to PPARγ agonist treatment is typicallytreated by withdrawing PPAR treatment.

Treatment of type 2 diabetes also typically includes physical exercise,weight control and dieting. While physical exercise and reductions indietary intake of calories will dramatically improve the diabeticcondition, compliance with this treatment is very poor because ofwell-entrenched sedentary lifestyles and excess food consumption,especially of foods containing high amounts of saturated fat. However,weight reduction and increased exercise are difficult for most peoplewith diabetes.

Abnormal glucose homeostasis is also associated both directly andindirectly with obesity, hypertension and dyslipidemias. Obesityincreases the likelihood of insulin resistance, and increases thelikelihood that the resulting insulin resistance will increase withincreasing body weight. Therefore, therapeutic control of glucosehomeostasis, lipid metabolism, obesity and hypertension are criticallyimportant in the clinical management and treatment of diabetes mellitus.

Obesity, which can be defined as a body weight more than 20% above theideal body weight, is a major health concern in Western societies. It isestimated that one person per three adults in the United States areoverweight or obese. Obesity is the result of a positive energy balance,as a consequence of increased ratio of caloric intake to energyexpenditure. The molecular factors regulating food intake and bodyweight balance are incompletely understood. [B. Staels et al., J. Biol.Chem. 270(27), 15958 (1995); F. Lonnquist et al., Nature Medicine 1(9),950 (1995)]. Although the genetic and/or environmental factors leadingto obesity are poorly understood, several genetic factors have beenidentified.

Epidemiological studies have shown that increasing degrees of overweightand obesity are important predictors of decreased life expectancy.Obesity causes or exacerbates many health problems, both independentlyand in association with other diseases. The medical problems associatedwith obesity, which can be serious and life-threatening, include type 2diabetes mellitus, hypertension, elevated plasma insulin concentrations,insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast,prostate, kidney and colon cancer, osteoarthritis; respiratorycomplications, such as obstructive sleep apnea, gallstones,arteriosclerosis, heart disease, abnormal heart rhythms, and heartarrythmias (Kopelman, P. G., Nature 404, 635-643 (2000)). Obesity isalso associated with metabolic syndrome, cardiac hypertrophy, inparticular left ventricular hypertrophy, premature death, and with asignificant increase in mortality and morbidity from stroke, myocardialinfarction, congestive heart failure, coronary heart disease, and suddendeath.

Abdominal obesity has been linked with a much higher risk of coronaryartery disease, and with three of its major risk factors: high bloodpressure, diabetes that starts in adulthood, and high levels of fats(lipids) in the blood. Losing weight dramatically reduces these risks.Abdominal obesity is further closely associated with glucoseintolerance, hyperinsulinemia, hypertriglyceridemia, and other disordersassociated with metabolic syndrome (syndrome X), such as raised highblood pressure, decreased levels of high density lipoproteins (HDL) andincreased levels of very low density lipoproteins (VLDL) (Montague etal., Diabetes, 2000, 49: 883-888).

Obesity and obesity-related disorders, such as diabetes, are oftentreated by encouraging patients to lose weight by reducing their foodintake or by increasing their exercise level, thereby increasing theirenergy output. A sustained weight loss of 5% to 10% of body weight hasbeen shown to improve the comorbidities associated with obesity, such asdiabetes, and can lead to improvement of obesity-related disorders suchas diabetes, left ventricular hypertrophy, osteoarthritis, and pulmonaryand cardiac dysfunction.

Weight loss drugs used for the treatment of obesity include or list at(Davidson, M. H. et al. (1999) JAMA 281:235-42), dexfenfluramine (GuyGrand, B. et al. (1989) Lancet 2:1142-5), sibutramine (Bray, G. A. etal. (1999) Obes. Res. &:189-98) and phentermine (Douglas, A. et al.(1983) Int. J. Obes. 7:591-5). However, the side effects of these drugsand anti-obesity agents may limit their use. Dexfenfluramine waswithdrawn from the market because of suspected heart valvulopathy;orlistat is limited by gastrointestinal side effects; and the use ofsibutramine is limited by its cardiovascular side effects which have ledto reports of deaths and its withdrawal from the market in Italy.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type 1 diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type2 diabetes). The compositions of the present invention are useful fortreating both Type 1 and Type 2 diabetes. The compositions areespecially effective for treating Type 2 diabetes. The compositions ofthe present invention are also useful for treating and/or preventinggestational diabetes mellitus.

Treatment of diabetes mellitus refers to the administration of acompound or combination of the present invention to treat diabetes. Oneoutcome of treatment may be decreasing the glucose level in a subjectwith elevated glucose levels. Another outcome of treatment may bedecreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment is decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentis decreasing LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment is increasing HDL cholesterol in asubject with low HDL cholesterol levels. Another outcome of treatment isincreasing insulin sensitivity. Another outcome of treatment may beenhancing glucose tolerance in a subject with glucose intolerance. Yetanother outcome of treatment maybe decreasing insulin resistance in asubject with increased insulin resistance or elevated levels of insulin.

The compounds or combined compositions of the present invention areuseful for the prevention of diabetes.

The term “hypertension” as used herein includes essential, or primary,hypertension wherein the cause is not known or where hypertension is dueto greater than one cause, such as changes in both the heart and bloodvessels; and secondary hypertension wherein the cause is known. Causesof secondary hypertension include, but are not limited to obesity;kidney disease; hormonal disorders; use of certain drugs, such as oralcontraceptives, corticosteroids, cyclosporin, and the like. The term“hypertension” encompasses high blood pressure, in which both thesystolic and diastolic pressure levels are elevated, and isolatedsystolic hypertension, in which only the systolic pressure is elevatedto greater than or equal to 140 mm Hg, while the diastolic pressure isless than 90 mm Hg. One outcome of treatment is decreasing bloodpressure in a subject with high blood pressure.

Dyslipidemias or disorders of lipid metabolism, include variousconditions characterized by abnormal concentrations of one or morelipids (i.e. cholesterol and triglycerides), and/or apolipoproteins(i.e., apolipoproteins A, B, C and E), and/or lipoproteins (i.e., themacromolecular complexes formed by the lipid and the apolipoprotein thatallow lipids to circulate in blood, such as LDL, VLDL and IDL).Hyperlipidemia is associated with abnormally high levels of lipids, LDLand VLDL cholesterol, and/or triglycerides.

The term “metabolic syndrome”, also known as syndrome X, is defined inthe Third Report of the National Cholesterol Education Program ExpertPanel on Detection, Evaluation and Treatment of High Blood Cholesterolin Adults (ATP-III). E. S. Ford et al., JAMA, vol. 287 (3), Jan. 16,2002, pp 356-359. Briefly, a person is defined as having metabolicsyndrome if the person has three or more of the following symptoms:abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high bloodpressure, and high fasting plasma glucose. The criteria for these aredefined in ATP-III.

The term “left venticular hypertrophy” (LVH) as used herein includesthree patterns of left ventricular hypertrophy that have been identifiedbased on left ventricular mass index (LVMI=left ventricular mass ingrams divided by body surface area in meters2) and relative wallthickness (RWT=2× posterior wall thickness/left ventricular enddiastolic diameter). Concentric LVH is typically exemplified by a leftventricular mass index of 144 and a relative wall thickness of 0.52;eccentric LVH is typically exemplified by a left ventricular mass indexof 136 and a relative wall thickness of 0.38; and concentric leftventricular remodeling which is typically exemplified by a LVMI of 93and a relative wall thickness of 0.49. Normal LVMI are typically 85 andnormal RWT approximately 0.36. Patients with concentric left ventricular(LV) remodeling have a cardiovascular risk intermediate between thosewith normal left ventricular structure and those with left ventricularhypertrophy.

One outcome of treatment of diabetes while minimizing cardiachypertrophy, or left ventricular hypertrophy, may be a decrease inventricular mass. Another outcome of treatment of diabetes whileminimizing cardiac hypertrophy or left ventricular hypertrophy may be adecrease in the rate of increase of ventricular mass. Another outcome oftreatment of diabetes while minimizing cardiac hypertrophy or leftventricular hypertrophy may be a decrease in ventricular wall thickness.Another outcome of treatment of diabetes while minimizing cardiachypertrophy of left ventricular hypertrophy may be the decrease in therate of increase in ventricular wall thickness.

The term “obesity” as used herein is a condition in which there is anexcess of body fat. The operational definition of obesity is based onthe BodyMass Index (BMI), which is calculated as body weight per heightin meters squared (kg/m²). “Obesity” refers to a condition whereby anotherwise healthy subject has a Body Mass Index (BMI) greater than orequal to 30 kg/m², or a condition whereby a subject with at least oneco-morbidity has a BMI greater than or equal to 27 kg/m². An “obesesubject” is an otherwise healthy subject with a Body Mass Index (BMI)greater than or equal to 30 kg/m² or a subject with at least oneco-morbidity with a BMI greater than or equal to 27 kg/m². A “subject atrisk of obesity” is an otherwise healthy subject with a BMI of 25 kg/m²to less than 30 kg/m² or a subject with at least one co-morbidity with aBMI of 25 kg/m² to less than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity, that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asia-Pacific, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes, non-insulin dependent diabetes mellitus-type 2,diabetes associated with obesity, impaired glucose tolerance, impairedfasting glucose, insulin resistance syndrome, dyslipidemia,hypertension, hypertension associated with obesity, hyperuricacidemia,gout, coronary artery disease, myocardial infarction, angina pectoris,sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebralinfarction, cerebral thrombosis, transient ischemic attack, orthopedicdisorders, arthritis deformans, lumbodynia, emmeniopathy, andinfertility. In particular, co-morbidities include: hypertension,hyperlipidemia, dyslipidemia, glucose intolerance, cardiovasculardisease, sleep apnea, diabetes mellitus, and other obesity-relatedconditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the compounds or combinations of the present inventionto reduce or maintain the body weight of an obese subject. One outcomeof treatment may be reducing the body weight of an obese subjectrelative to that subject's body weight immediately before theadministration of the compounds or combinations of the presentinvention. Another outcome of treatment may be preventing body weightregain of body weight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of treatment may be decreasing theoccurrence of and/or the severity of obesity-related diseases. Thetreatment may suitably result in a reduction in food or calorie intakeby the subject, including areduction in total food intake, or areduction of intake of specific components of the diet such ascarbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

Prevention of obesity and obesity-related disorders refers to theadministration of the compounds or combinations of the present inventionto reduce or maintain the body weight of a subject at risk of obesity.One outcome of prevention may be reducing the body weight of a subjectat risk of obesity relative to that subject's body weight immediatelybefore the administration of the compounds or combinations of thepresent invention. Another outcome of prevention may be preventing bodyweight regain of body weight previously lost as a result of diet,exercise, or pharmacotherapy. Another outcome of prevention may bepreventing obesity from occurring if the treatment is administered priorto the onset of obesity in a subject at risk of obesity. Another outcomeof prevention may be decreasing the occurrence and/or severity ofobesity-related disorders if the treatment is administered prior to theonset of obesity in a subject at risk of obesity. Moreover, if treatmentis commenced in already obese subjects, such treatment may prevent theoccurrence, progression or severity of obesity-related disorders, suchas, but not limited to, arteriosclerosis, Type 2 diabetes, polycysticovary disease, cardiovascular diseases, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The term “atherosclerosis” as used herein encompasses vascular diseasesand conditions that are recognized and understood by physicianspracticing in the relevant fields of medicine. Atheroscleroticcardiovascular disease, coronary heart disease (also known as coronaryartery disease or ischemic heart disease), cerebrovascular disease andperipheral vessel disease are all clinical manifestations ofatherosclerosis and are therefore encompassed by the terms“atherosclerosis” and “atherosclerotic disease.” The combinationcomprised of a therapeutically effective amount of an anti-obesity agentin combination with a therapeutically effective amount of ananti-diabetic agent may be administered to prevent or reduce the risk ofoccurrence, or recurrence where the potential exists, of a coronaryheart disease event, a cerebrovascular event, or intermittentclaudication. Coronary heart disease events are intended to include CHDdeath, myocardial infarction (i.e., a heart attack), and coronaryrevascularization procedures. Cerebrovascular events are intended toinclude ischemic or hemorrhagic stroke (also known as cerebrovascularaccidents) and transient ischemic attacks. Intermittent claudication isa clinical manifestation of peripheral vessel disease. The term“atherosclerotic disease event” as used herein is intended to encompasscoronary heart disease events, cerebrovascular events, and intermittentclaudication. It is intended that persons who have previouslyexperienced one or more non-fatal atherosclerotic disease events arethose for whom the potential for recurrence of such an event exists.

Circadian rhythms affect a variety of physiological parameters:rest-activity, sleep-wake cycles, body temperature, rhythms in hormonelevels, oscillations in general physiology and the like. When theseparameters are out of synchrony with the daily clock, a circadian rhythmimbalance occurs which can affect physiology, performance on a varietyof tasks and one's emotional well being. The present invention isuseful, for example, in the prevention or treatment of conditionsassociated with circadian rhythmicity as well as mental and physicaldisorders associated with travel across time zones and with rotatingshift-work schedules.

In another embodiment, the present invention provides a method for theprevention or treatment of a circadian rhythm disorder in a mammal,including time-zone change (jet-lag) syndrome, shift-work sleepdisorder, delayed sleep-phase syndrome, advanced sleep-phase syndrome,and non-24-hour sleep-wake disorder, which comprises administering tothe mammal an effective amount of a NPY Y5 receptor antagonist.

In another embodiment, the present invention provides a method forshortening the time of re-entrainment (return to normal entrainment ofthe circadian rhythms; synchronized to the environmental light-darkcycle) in a subject following a shift in the sleep-wake cycle whichcomprises administering to the subject an appropriate amount of a NPY Y5antagonist.

In another embodiment, the present invention provides a method foralleviating the effects of jet lag in a traveler, especially a mammal,which comprises administering to the traveler an alertness increasingamount of a NPY Y5 antagonist. The purpose of this embodiment is toassist the body to adjust physiologically to the changes in sleep andfeeding patterns when crossing several time zones.

In another more preferred embodiment, the present invention provides amethod for resetting the internal circadian clock in a subject to matchthe subject's current activity/sleep cycle. For example shift workerschanging from a day to a night shift or vice versa, which comprisesadministering to the subject an appropriate amount of a NPY Y5antagonist.

The present invention is further directed to the use of NPY Y5antagonist, for enhancing or improving sleep quality as well aspreventing and treating sleep disorders and sleep disturbances in amammal. In particular, the present invention provides a method forenhancing or improving sleep quality by increasing sleep efficiency andaugmenting sleep maintenance. In addition, the present inventionprovides a method for preventing and treating sleep disorders and sleepdisturbances in a mammal which comprising the administration of a NPY Y5antagonist. The present invention further provides a pharmaceuticalcomposition for enhancing or improving sleep quality and increasingsleep efficiency and sleep maintenance. The present invention is usefulfor the treatment of sleep disorders, including Disorders of Initiatingand Maintaining Sleep (insomnias) (“DIMS”) which can arise frompsychophysiological causes, as a consequence of psychiatric disorders(particularly related to anxiety), from drugs and alcohol use and abuse(particularly during withdrawal stages), childhood onset DIMS, nocturnalmyoclonus and restless legs and non specific REM disturbances as seen inageing.

The following outcomes in a subject which are provided by the presentinvention may be correlated to enhancement in sleep quality: an increasein the value which is calculated from the time that a subject sleepsdivided by the time that a subject is attempting to sleep; a decrease insleep latency (the time it takes to fall asleep); a decrease in thenumber of awakenings during sleep; a decrease in the time spent awakefollowing the initial onset of sleep; an increase in the total amount ofsleep; an increase the amount and percentage of REM sleep; an increasein the duration and occurrence of REM sleep; a reduction in thefragmentation of REM sleep; an increase in the amount and percentage ofslow-wave (i.e. stage 3 or 4) sleep; an increase in the amount andpercentage of stage 2 sleep; a decrease in the number of awakenings,especially in the early morning; an increase in daytime alertness; andincreased sleep maintenance. Secondary outcomes which may be provided bythe present invention include enhanced cognitive function and increasedmemory retention. A “method forenhancing the quality of sleep” refers toa method that results in outcomes in a subject which may be correlatedto enhancement in sleep quality, including, but not limited to, theoutcomes correlated to enhancement of sleep quality as defined above.

The present invention is further useful for the prevention and treatmentof sleep disorders and sleep disturbances including sleep problemsassociated with insomnia, hypersomnia, sleep apnea, narcolepsy,nocturnalmyoclonus, REM sleep interruptions, jet-lag, shift workers'sleep disturbances, dysomnias, night terror, night eating syndrome,insomnias associated with depression or with emotional/mood disorders,dysfunctions associated with sleep (parasomnias), as well as sleepwalking and enuresis, as well as sleep disorders which accompany aging.Sleep disorders and sleep disturbances are generally characterized bydifficulty in initiating or maintaining sleep or in obtaining restful orenough sleep.

In addition, certain drugs may also cause reductions in REM sleep as aside effect and the present invention may be used to correct those typesof sleeping disorders as well. The present invention would also be ofbenefit in the treatment of syndromes such as fibromyalgia which aremanifested by non-restorative sleep and muscle pain or sleep apnea whichis associated with respiratory disturbances during sleep. It will beclear to one skilled in the art that the present invention is notlimited to just sleep disorders and sleep disturbances, but isapplicable to a wide variety of conditions which result from adiminished quality of sleep.

The present invention is also concerned with treatment and prevention ofthese conditions, and with the use of a NPY Y5 antagonist, combinations,and compositions thereof, for the manufacture of a medicament useful fortreating or preventing these conditions.

In the present invention, it is preferred that the subject mammal is ahuman. Although the present invention is applicable both old and youngpeople, it may find greater application in elderly people. Further,although the invention may be employed to enhance the sleep of healthypeople, it may be especially beneficial for enhancing the sleep qualityof people suffering from sleep disorders or sleep disturbances.

The compositions of the present invention may be used in combinationwith other drugs that may also be useful in the treatment, prevention,or control of disorders, such as hypertension, hypertension associatedwith obesity, hypertension-related disorders, cardiac hypertrophy, leftventricular hypertrophy, and metabolic syndrome, obesity andobesity-related disorders, for which compounds comprising thecompositions are useful. Such other drugs may be administered, by aroute and in an amount commonly used therefore, contemporaneously orsequentially with a composition of the present invention. When acomposition of the present invention is used contemporaneously with oneor more other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the composition of the present inventionis preferred. However, the combination therapy also includes therapiesin which the composition of the present invention and one or more otherdrugs are administered on different overlapping schedules. It is alsocontemplated that when used in combination with one or more other activeingredients, the composition of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a composition of the present invention.

Examples of other active ingredients that may be administered incombination with a composition of the present invention, and eitheradministered separately or in the same pharmaceutical composition,include, but are not limited to:

(a) anti-diabetic agents such as (i) PPARγ agonists such as glitazones(e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555);pioglitazone; rosiglitazone; troglitazone; BRL49653; CLX-0921; 5-BTZD,and the like), and GW-0207, LG-100641, and LY-300512, and the like; (ii)biguanides such as buformin; metformin; and phenformin, and the like;(iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (iv)sulfonylureas such as acetohexamide; chlorpropamide; diabinese;glibenclamide; glipizide; glyburide; glimepiride; gliclazide;glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide, andthe like; (v) meglitinides such as repaglinide, andnateglinide,andthelike; (vi) alphaglucoside hydrolase inhibitors such as acarbose;adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q;salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the like;(vii) alpha-amylase inhibitors such as tendamistat, trestatin, andAl-3688, and the like; (viii) insulin secretagogues such as linogliride;and A-4166, and the like; (ix) fatty acid oxidation inhibitors, such asclomoxir, and etomoxir, and the like; (x) A2 antagonists, such asmidaglizole; isaglidole; deriglidole; idazoxan; earoxan; and fluparoxan,and the like; (xi) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lenteandultralente); Lys-Proinsulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)—NH₂), and the like; (xii)non-thiazolidinediones such as JT-501, and farglitazar(GW-2570/GI-262579), and the like; (xiii) PPARα/γ dual agonists such asMK-0767, CLX-0940, GW-1536, GW1929, GW-2433, KRP-297, L-796449, LR-90,and SB 219994, and the like; (xiv) other insulin sensitizing drugs; and(xv) VPAC2 receptor agonists;

(b) lipid lowering agents such as (i) bile acid sequestrants such as,cholestyramine, colesevelem, colestipol, dialkylaminoalkyl derivativesof a cross-linked dextran; Colestid®; LoCholest®; and Questran®, and thelike; (ii) HMG-CoA reductase inhibitors such as atorvastatin,itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin,rosuvastatin, simvastatin, and ZD-4522, and the like; (iii) HMG-CoAsynthase inhibitors; (iv) cholesterol absorption inhibitors such asstanol esters, beta-sitosterol, sterol glycosides such as tiqueside; andazetidinones such as ezetimibe, and the like; (v) acyl coenzymeA-cholesterol acyl transferase (ACAT) inhibitors such as avasimibe,eflucimibe, KY505, SMP 797, and the like; (vi) CETP inhibitors such asJTT 705, torcetrapib, CP 532,632, BAY63-2149, SC 591, SC 795, and thelike; (vii) squalene synthetase inhibitors; (viii) anti-oxidants such asprobucol, and the like; (ix) PPARα agonists such as beclofibrate,benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate,gemcabene, and gemfibrozil, GW 7647, BM 170744, LY518674; and otherfibric acid derivatives, such as Atromid®, Lopid® and Tricor®, and thelike; (x) FXR receptor modulators such as GW4064, SR 103912, and thelike; (xi) LXR receptor such as GW 3965, T9013137, and XTCO179628, andthe like; (xii) lipoprotein synthesis inhibitors such as niacin; (xiii)renin angiotensin system inhibitors; (xiv) PPARδ partial agonists; (xv)bile acid reabsorption inhibitors, such as BARI 1453, SC435, PHA384640,S8921, AZD7706, and the like; (xvi) PPARδ agonists such as GW501516, andGW590735, and the like; (xvii) triglyceride synthesis inhibitors;(xviii) microsomal triglyceride transport (MTTP) inhibitors, such asinplitapide, LAB687, and CP346086, and the like; (xix) transcriptionmodulators; (xx) squalene epoxidase inhibitors; (xxi) low densitylipoprotein (LDL) receptor inducers; (xxii) platelet aggregationinhibitors; (xxiii) 5-LO or FLAP inhibitors; and (xiv) niacin receptoragonists; and

(c) anti-hypertensive agents such as (i) diuretics, such as thiazides,including chlorthalidone, chlorthiazide, dichlorophenamide,hydroflumethiazide, indapamide, and hydrochlorothiazide; loop diuretics,such as bumetanide, ethacrynic acid, furosemide, and torsemide;potassium sparing agents, such as amiloride, and triamterene; andaldosterone antagonists, such as spironolactone, epirenone, and thelike; (ii) beta-adrenergic blockers such as acebutolol, atenolol,betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol,celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol,penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol,andtimolol, andthelike; (iii) calcium channel blockers such asamlodipine, aranidipine, azelnidipine, barnidipine, benidipine,bepridil, cinaldipine, clevidipine, diltiazem, efonidipine, felodipine,gallopamil, isradipine, lacidipine, lemildipine, lercanidipine,nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine,nitrendipine, manidipine, pranidipine, and verapamil, and the like; (iv)angiotensin converting enzyme (ACE) inhibitors such as benazepril;captopril; cilazapril; delapril; enalapril; fosinopril; imidapril;losinopril; moexipril; quinapril; quinaprilat; ramipril; perindopril;perindropril; quanipril; spirapril; tenocapril; trandolapril, andzofenopril, and the like; (v) neutral endopeptidase inhibitors such asomapatrilat, cadoxatril and ecadotril, fosidotril, sampatrilat, AVE7688,ER4030, and the like; (vi) endothelin antagonists such as tezosentan,A308165, and YM62899, and the like; (vii) vasodilators such ashydralazine, clonidine, minoxidil, and nicotinyl alcohol, and the like;(viii) angiotensin II receptor antagonists such as candesartan,eprosartan, irbesartan, losartan, pratosartan, tasosartan, telmisartan,valsartan, and EXP-3137, FI6828K, and RNH6270, and the like; (ix) α/βadrenergic blockers as nipradilol, arotinolol and amosulalol, and thelike; (x) alpha 1 blockers, such as terazosin, urapidil, prazosin,bunazosin, trimazosin, doxazosin, naftopidil, indoramin, WHIP 164, andXEN010, and the like; (xi) alpha 2 agonists such as lofexidine,tiamenidine, moxonidine, rilmenidine and guanobenz, and the like; and(xii) aldosterone inhibitors, and the like; and

(d) anti-obesity agents, such as (i) 5HT (serotonin) transporterinhibitors, such as paroxetine, fluoxetine, fenfluramine, fluvoxamine,sertraline, and imipramine; (ii) NE (norepinephrine) transporterinhibitors, such as GW 320659, despiramine, talsupram, and nomifensine;(iii) CB-1 (cannabinoind-1 receptor) antagonist/inverse agonists, suchas rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), BAY65-2520 (Bayer), and SLV 319 (Solvay), and those disclosed in U.S. Pat.Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941 and 6,028,084; and WO 96/33159, WO 98/33765, WO 98/43636, WO98/43635, WO 01/09120, WO 01.96330, WO 98/31227, WO 98/41519, WO98/37061, WO 00/10967, WO 00/10968, WO 97/29079, WO 99/02499, WO01/58869, WO 02/076949, WO 01/64632, WO 01/64633, WO 01/64634, WO03/006007, and WO 03/007887; and EPO Application No. EP-658546; (iv)ghrelin antagonists, such as those disclosed in WO 01/87335, and WO02/08250; (v) H3 (histamine H3) antagonist/inverse agonists, such asthioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andA331440, and those disclosed in WO 02/15905; andO-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et al.,Pharmazie, 55:349-55 (2000)), piperidine-containing histamineH3-receptor antagonists (Lazewska, D. et al., Pharmazie,56:927-32(2001), benzophenone derivatives and related compounds (Sasse,A. et al., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)),and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)); (vi) melanin-concentrating hormone 1 receptor (MCH1R)antagonists, such as T-226296 (Takeda), SNP-7941 (Synaptic), and thosedisclosed in WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO02/094799, WO 03/004027, and Japanese Patent Application No. JP13226269;(vii) MCH2R (melanin concentrating hormone 2R) agonist/antagonists;(viii) NPY1 (neuropeptide Y Y1) antagonists, such as BIBP3226,2-[1-(5-chloro-3-isopropyloxycarbonylaminophenyl)ethylamino1-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholi nopyridine,BIBO 3304, LY-357897, CP-671906, and GI-264879A; and those disclosed inU.S. Pat. No. 6,001,836; and WO 96/14307, WO 01/23387, WO 99/51600, WO01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (ix) NPY5(neuropeptide YY5) antagonists, such as L-152,804, GW-569180A,GW-594884A, GW-587081X, GW-548118X; FR 235,208; FR226928, FR 240662,FR252384; 1229U91, GI-264879A, CGP71683A, LY-377897, LY366377,PD-160170, SR-120562A, SR-120819A, JCF-104, and H409/22; and thosecompounds disclosed in U.S. Pat. Nos. 6,140,354, 6,191,160, 6,258,837,6,313,298, 6,337,332, 6,329,395, and 6,340,683; 6,326,375; 6,329,395;6,337,332; 6,335,345; European Patent Nos. EP-01010691, and EP-01044970;and PCT International Patent Publication Nos. WO 97/19682, WO 97/20820,WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/107409, WO00/185714, WO 00/185730, WO 00/64880, WO 00/68197, WO 00/69849, WO01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO01/62737, WO 01/62738, WO 01/09120, WO 02/20488, WO 02/22592, WO02/48152, WO 02/49648 and WO 02/094789; and Norman et al., J. Med. Chem.43:4288-4312 (2000); (x) leptin, such as recombinant human leptin(PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin(Amgen); (xi) leptin derivatives, such as those disclosed in U.S. Pat.Nos. 5,552,524; 5,552,523; 5,552,522; 5,521,283; and PCT InternationalPublication Nos. WO 96/23513; WO 96/23514; WO 96/23515; WO 96/23516; WO96/23517; WO 96/23518; WO 96/23519; and WO 96/23520; (xii) opioidantagonists, such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone,and naltrexone; and those disclosed in WO 00/21509; (xiii) orexinantagonists, such as SB-334867-A; and those disclosed in WO 01/96302, WO01/68609, WO 02/51232, WO 02/51838, and WO 03/023561; (xiv) BRS3(bombesin receptor subtype 3) agonists; (xv) CCK-A (cholecystokinin-A)agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 andSR146131, and those disclosed in U.S. Pat. No. 5,739,106; (xvi) CNTF(ciliary neurotrophic factors), such as GI-181771 (Glaxo-SmithKline);SR146131 (Sanofi Synthelabo); butabindide; and PD170,292, PD 149164(Pfizer); (xvii) CNTF derivatives, such as axokine (Regeneron); and WO94/09134, WO 98/22128, and WO 99/43813; (xviii) GHS (growth hormonesecretagogue receptor) agonists, such as NN703, hexarelin, MK-0677,SM-130686, CP-424,391, L-692,429 and L-163,255, and those disclosed inU.S. Pat. No. 6,358,951, U.S. Patent Application Nos. 2002/049196 and2002/022637; and WO 01/56592, and WO 02/32888; (xix) 5HT2c (serotoninreceptor 2c) agonists, such as BVT933, DPCA37215, IK264; PNU22394;WAY161503, R-1065, and YM 348; and those disclosed in U.S. Pat. No.3,914,250; and WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO02/44152; WO 02/51844, WO 02/40456, and WO 02/40457; (xx) Mc3r(melanocortin 3 receptor) agonists; (xxi) Mc4r (melanocortin 4receptor)agonists, such as CHIR86036 (Chiron); ME-10142, and ME-10145 (Melacure),and those disclosed in WO 99/64002, WO 00/74679, WO 01/991752, WO01/74844, WO 01/70708, WO 01/70337, WO 01/91752, WO 02/059095, WO02/059107, WO 02/059108, WO 02/059117, WO 02/12166, WO 02/11715, WO02/12178, WO 02/15909, WO 02/068387, WO 02/068388, WO 02/067869, WO03/007949, and WO 03/009847; (xxii) monoamine reuptake inhibitors, suchas sibutratmine (Meridia®/Reductil®) and a salt thereof, and thosecompounds disclosed in U.S. Pat. Nos. 4,746,680, 4,806,570, and5,436,272, and U.S. Patent Publication No. 2002/0006964, and WO01/27068, and WO 01/62341; (xxiii) serotonin reuptake inhibitors, suchas dexf enf luramine, fluoxetine, and those in U.S. Pat. No. 6,365,633,and WO 01/27060, and WO 01/162341; (xxiv) GLP-1 (glucagon-likepeptide 1) agonists; (xxv) Topiramate (Topimax®); (xxvi) phytopharmcompound 57 (CP 644,673); (xxvii) ACC2(acetyl-CoAcarboxylase-2)inhibitors; (xxviii) β3 (beta adrenergic receptor 3)agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243,GW 427353, Trecadrine, Zeneca D7114, and SR 59119A, and those disclosedin U.S. Patent Application Nos. 5,705,515, 5,451677; and WO 01/74782,and WO 02/32897; (xxix) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (xxx) DGAT2 (diacylglycerol acyltransferase 2)inhibitors;(xxxi) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75;(xxxii) PDE (phosphodiesterase) inhibitors, such as theophylline,pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide,rolipram, and cilomilast; (xxxiii) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS), and those disclosed in WO 02/15845; and JapanesePatent Application No. JP 2000256190; (xxxiv) UCP-1 (uncoupling protein1), 2, or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), and retinoic acid; and those disclosed in WO 99/00123;(xxxv) acyl-estrogens, such as oleoyl-estrone, disclosed in delMar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (xxxvi)glucocorticoid antagonists; (xxxvii) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors, such as BVT 3498, BVT 2733, and thosecompounds disclosed in WO 01/90091, WO 01/90090, WO 01/90092; (xxxviii)SCD-1 (stearoyl-CoA desaturase-1) inhibitors; (xxxix) dipeptidylpeptidase IV (DP-IV) inhibitors, such as isoleucine thiazolidide, valinepyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE999011, P9310/K364, VIP 0177, SDZ 274-444; and the compounds disclosedin WO 03/004498, WO 03/004496, EP1258476, WO 02/083128, WO 02/062764, WO03/000250, WO 03/002530, WO 03/002531, WO 03/002553, WO 03/002593, WO03/000180, and WO 03/000181; (xxxx) lipase inhibitors, such astetrahydrolipstatin (orlistat/Xenical®), Triton WR1339, RHC80267,lipstatin, teasaponin, and diethylumbelliferyl phosphate, FL-386,WAY-121898, Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactoneB, and RHC 80267, and those disclosed in WO 01/77094, and U.S. Pat. Nos.4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644,4,189,438, and 4,242,453; (xxxxi) fatty acid transporter inhibitors;(xxxxii) dicarboxylate transporter inhibitors; (xxxxiii) glucosetransporter inhibitors; (xxxxiv) phosphate transporter inhibitors;(xxxxv) melanocortin agonists, such as Melanotan II or those describedin WO 99/64002 and WO 00/746799; (xxxxvi) melanin concentrating hormoneantagonists; (xxxxvii) galanin antagonists; (xxxxviii) CCK agonists;(xxxxix) corticotropin-releasing hormone agonists; and (xxxxx)phosphodiesterase-3B (PDE3B) inhibitors; and the like.

The above combinations include combinations of a composition of thepresent invention not only with one other active compound, but also withtwo or more other active compounds. Non-limiting examples includecombinations of the compositions of the present invention with one, twoor more active compounds selected from lipid-lowering agents, andanti-hypertensive agents. Combinations of the compositions of thepresent invention with one, two or more active compounds selected fromlipid lowering agents, and anti-diabetic agents are useful to treat,control or prevent metabolic syndrome. In particular, compositionscomprising an anti-obesity agent and an anti-hypertensive agent, inaddition to an anti-diabetic agent and/or a lipid lowering agent will beuseful to synergistically. treat, control or prevent metabolic syndrome.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Examples are provided to illustrate the present inventionmore concretely, but they should not be construed as limiting theinvention in any way. The mass spectrum was determined by electron sprayionization (ESI) method.

EXAMPLE 1 Preparation of4-(2-naphthyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazolehydrochloride (1) Preparation of[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]carboxamidinehydrochloride

To a solution of spiro[isobenzofuran-1(3H),4′-piperidin]-3-onehydrochloride monohydrate (10.0 g, 38.9 mmol) in N,N-dimethylformamide(100 mL) were added 1H-pyrazole-1-carboxamidine hydrochloride (6.0 g,40.9 mmol) and diisopropylethylamine (14.2 mL, 81.5 mmol), and themixture was stirred at room temperature for 19 hours. The reactionsolution was concentrated in vacuo. Ethanol and diethyl ether were addedto the resulting residue, and the precipitates were collected byfiltration and dried to obtain the title compound (9.1 g, 78%).

(2) Preparation of 2-tosyloxy-2′-acetonaphthone

Acetonitrile solution (40 mL) containing 2-acetonaphthone (1.70 g, 9.99mmol) and [hydroxyl(tosyloxy)iodo]benzene (4.00 mg, 10.2 mmol) washeated under ref lux for 3 hours. The reaction mixture was cooled, andethyl acetate was added thereto. The reaction solution was washed withsaturated aqueous sodium bicarbonate solution, dried over anhydrousmagnesium sulfate, and concentrated in vacuo to remove the solvent toobtain the title compound (2.33 g, 68.5%).

(3) Preparation of4-(2-naphthyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazolehydrochloride

(Method 1)

N,N-Dimethylformamide solution (1 mL) containing[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]carboxamidinehydrochloride (100 mg, 0.355 mmol) and 2-tosyloxy-2′-acetonaphthone (130mg, 0.382 mmol) was added to potassium carbonate (150 mg, 1.09 mmol),and the mixture was stirred at 100° C. for 10 minutes. The reactionmixture was cooled, ethyl acetate was added thereto, and it was washedwith saturated aqueous sodium bicarbonate solution and saturated aqueousbrine, dried over anhydrous magnesium sulfate and concentrated in vacuoto remove the solvent. The resulting residue was dissolved in ethylacetate (20 mL) and to this solution was added 4N hydrochloricacid/ethyl acetate (0.5 mL); the mixture was stirred at room temperaturefor 30 minutes. The resulting precipitates were collected by filtrtionand dried to obtain the title compound (70.4 mg, 45.9%).

(Method 2)

N,N-dimethylformamide solution (1 mL) containing[3-oxospiro[isobenazofuran-1(3H),4′-piperidin]-1′-yl]carboxamidinehydrochloride (100 mg, 0.355 mmol) and 2-bromo-2′-acetonaphthone (88.4mg, 0.355 mmol) was added to potassium carbonate (150 mg, 1.09 mmol),and the mixture was stirred at 100° C. for 20 minutes. After thereaction mixture was cooled, ethyl acetate was added thereto. Themixture was washed with saturated aqueous sodium bicarbonate solutionand saturated aqueous brine, and the organic layer was dried overanhydrous magnesium sulfate, and then concentrated in vacuo. Theresulting residue was dissolved in ethyl acetate (20 mL), and to thissolution was added 4N hydrochloric acid/ethyl acetate (0.5 mL). Thesolution was stirred at room temperature for 30 minutes, and theresulting precipitates were collected by filtration to obtain the titlecompound (30.2 mg, 19.7%).

¹HNMR(300 MHz, DMSO-d₆, δppm): 1.8-1.9(2H, m), 2.4-2.6(2H, m),3.5-3.7(2H, m), 4.2-4.4(2H, m), 7.5-7.7(3H, m), 7.7-8.0(7H, m), 8.01(1H,d, J=8.8 Hz), 8.36(1H, s), 12.7(1H, brs), 13.0(1H, brs); mass spectrum(ESI): 396(M+H).

The following compounds were prepared according to a method similar tothe procedure of Example 1.

EXAMPLE 2 4-(4-bromophenyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazole hydrochloride

¹HNMR(300 MHz, DMSO-d₆, δppm): 1.76-1.87(2H, m), 2.35-2.49(2H, m),3.46-3.60(2H, m), 4.17-4.29(2H, m), 7.60-7.82(8H, m), 7.82(1H, d, J=7.6Hz); mass spectrum (ESI): 424,426(M+H)

EXAMPLE 32-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-4-(3-trifluoromethylphenyl)-1H-imidazole

¹HNMR(300 MHz, CDCl₃, δppm): 1.75-1.87(2H, m), 2.25-2.40(2H, m),3.44-3.58(2H, m), 3.92-4.03(2H, m), 7.08(1H, s), 7.33-7.75(5H, m),7.80-7.97(3H, m); mass spectrum (ESI): 414(M+H)

EXAMPLE 44-(4-biphenylyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazolehydrochloride

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.79-1.90(2H, m) 2.38-2.53(2H, m),3.49-3.62(2H, m), 4.20-4.31(2H, m), 7.36-7.44(1H, m), 7.46-7.54(2 H, m),7.60-7.68(1H, m), 7.70-7.94(10H, m); mass spectrum (ESI): 422(M+H)

EXAMPLE 54-(3-biphenylyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazolehydrochloride

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.73-1.87(2H, m), 2.33-2.49(2H, m),3.36-3.50(2H, m), 4.13-4.25(2H, m), 7.36-7.44(1H, m), 7.47-7.70(6 H, m),7.72-7.90(6H, m), 8.07(1H, s); mass spectrum(ESI): 422(M+H)

EXAMPLE 62-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-4,5-diphenyl-1H-imidazolehydrochloride

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.68-1.80(2H, m) 2.23-2.40(2H, m),3.15-3.28(2H, m), 4.07-4.18(2H, m), 7.09-7.20(1H, m), 7.21-7.52(9 H, m),7.58-7.66(1H, m), 7.77-7.88(3H, m); mass spectrum(ESI): 422(M+H)

EXAMPLE 74-(4-fluorophenyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(3-pyridyl)-1H-imidazolehydrochloride

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.70-1.82(2H, m), 2.26-2.42(2H, m),3.17-3.31(2H, m), 4.07-4.19(2H, m), 7.13(1H, t, J=9.2 Hz), 7.21-7.33(2H,m), 7.36-7.55(3H, m), 7.59-7.67(1H, m), 7.72-7.91(3H, m), 8.32-8.46(1H,m), 8.67-8.65(1H, m); mass spectrum(ESI): 441(M+H)

EXAMPLE 84-methyl-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-phenyl-1H-imidazolehydrochloride

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.65-1.77(2H, m), 2.17-2.40(5H, m),3.07-3.23(2H, m), 3.90-4.10(2H, m), 7.07-7.18(1H, m), 7.28-7.48(3 H, m),7.55-7.66(2H, m), 7.72-7.90(3H, m); mass spectrum(ESI): 360(M+H)

EXAMPLE 94-(3-methoxyphenyl)-2-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-imidazolehydrochloride

¹HNMR (300MHz, CDCl₃, δppm): 1.75-1.90(2H, m), 2.25-2.40(2H, m),3.42-3.59(2H, m), 3.85(3H, s), 3.91-4.05(2H, m), 6.76(1H, dd, J=2.5 Hz,9.1 Hz), 7.11-7.35(3H, m), 7.40(1H, d, J=7.5 Hz), 7.55(1H, t, J=7.5H z),7.68(1H, t, J=7.5 Hz), 7.91(1H, d, J=7.5 Hz); mass spectrum(ESI):376(M+H)

EXAMPLE 10 Preparation oftrans-4-(2-naphthyl)-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-1H-imidazole(1) Preparation oftrans-N-(2-naphthoylmethyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

To a solution oftrans-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxylic acid(123 mf, 0.5 mmol) in chloroform (5 mL) were added2-amino-2′-acetonaphthone hydrochloride (111 mg, 0.5 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg, 1mmol) and triethylamine (0.139 mL, 1 mmol), and the mixture was stirredat room temperature for 18 hours. The reaction solution was distributedusing water and ethyl acetate, and the organic layer was dried overanhydrous magnesium sulfate. After removal of the solvent by evaporationin vacuo, the residue was purified by a silica gel column chromatography(hexane:ethyl acetate=2:1 to 1:1) to obtain the title compound (50.7 mg,76%).

(2) Preparation oftrans-4-(2-naphthyl)-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-1H-imidazole

To a solution oftrans-N-(2-naphthoylmethyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide(152 mg, 0.37 mmol) in acetic acid (2 ml) was added ammonium acetate(848 mg, 11 mmol), and the mixture was stirred at 110° C. for 16 hours.After the reaction solution was cooled, it was concentrated in vacuo,and the residue was neutralized using saturated aqueous sodiumbicarbonate solution, and extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate and concentrated invacuo to remove the solvent. The residue was purified by a preparativethin layer chromatography (chloroform:ethyl acetate=2:1) to obtain thetitle compound (49.9 mg, 34%).

¹HNMR (300 MHz, CDCl₃, δppm): 1.70-1.90(2H, m), 2.20-2.50(6H, m)3.19-3.30(1H, m), 7.40-7.53(5H, m), 7.58-7.65(1H, m), 7.76-7.93(5H, m),8.10-8.40(1H, m); mass spectrum (ESI): 395(M+H)

The following compounds were prepared according to a method similar tothe procedure of Example 10.

EXAMPLE 11trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-4-(3-trifluoromethylphenyl)-1H-imidazole

¹HNMR (300 MHz, CDCl₃, δppm): 1.70-1.90(2H, m), 2.17-2.60(6H, m),3.20-3.30(1H, m), 7.36(1H, s), 7.45-7.55(4H, m), 7.65(1H, d, J=7.2 Hz),7.88(1H, d, J=7.2 Hz), 7.97(1H, brs), 8.10(1H, brs); mass spectrum(ESI): 413(M+H)

EXAMPLE 12trans-2-(2-naphthyl)-4-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-imidazole(1) Preparation of methyltrans-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]ketone

To a solution oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (308 mg, 1.2 mmol) in thionyl chloride (2 mL) was added one drop ofN,N-dimethylformamide, and the mixture was stirred for 4 hours at reflux under a nitrogen atmosphere. The reaction solution was concentratedin vacuo, and chloroform was added to the residue. The solution wasconcentrated in vacuo and dried to obtain a crude acid chloride (453mg). Diethyl ether solution (0.62 mL, 1.9 mmol) containing 3N methylmagnesium bromide was added dropwise to tetrahydrofuran solution (6 mL)containing the crude acid chloride (226 mg) and copper(I) iodide (118mg, 0.62 mmol) at −78° C. over 30 minutes under a nitrogen atmosphere,and then the temperature was raised to 0° C., and the mixture wasstirred for one hour. Saturated aqueous ammonium chloride solution wasadded to the reaction solution, followed by extraction with chloroform.After the organic layer was washed successively with saturated aqueousammonium chloride, saturated aqueous sodium carbonate and saturatedbrine, it was dried over anhydrous magnesium sulfate. The residueobtained by evaporation of the solvent in vacuo was purified by a silicagel column chromatography (C-300, ethyl acetate:hexane=2:1) to obtainthe title compound (119 mg, 78% yield of two steps).

(2) Preparation of bromomethyltrans-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]ketone

To a solution of methyltrans-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]ketone(50 mg, 0.20 mmol) in methanol (2 mL) was added dioxane bromide (76 mg,0.31 mmol), and the mixture was stirred at room temperature for 15 hoursunder a nitrogen atmosphere. The reaction solution was diluted withethyl acetate, washed with water and aqueous sodium sulfite, and driedover anhydrous magnesium sulfate. The solvent was removed by evaporationin vacuo to obtain the title compound (75 mg). The product was used inthe subsequent step without further purification.

(3) Preparation oftrans-2-(2-naphthyl)-4-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohhexan]-4′-yl]-1H-imidazole

Potassiumcarbonate (21 mg, 0.16 mmol) was added to dioxane solution(0.77 mL) containing 2-naphthamidine (18 mg, 0.077 mmol) and bromomethyltrans-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]ketone(25 mg), and the mixture was stirred at room temperature for 45 minutesunder a nitrogen atmosphere, and at 100° C. for further 2 hours. Thereaction solution was cooled to room temperature, diluted with ethylacetate, and washed with water and saturated brine. After the solutionwas dried over anhydrous magnesium sulfate, it was concentrated in vacuoto remove the solvent, and the resulting residue was purified by asilica gel column chromatography (C-300, ethyl acetate:hexane=2:1) and apreparative thin layer chromatography (ethyl acetate:hexane=2:1) toobtain the title compound (6.4 mg, 21%).

¹HNMR (400 MHz, CD₃OD, δppm): 2.05-2.20(4H, m), 2.21-2.40(4H, m),3.08-3.20(1H, m), 7.16(1H, s), 7.46-7.54(2H, m), 7.83-7.89(2H, m),7.90-7.96(2H, m), 7.99-8.04(1H, m), 8.34(1H, s), 8.83(1H, d, J=4.8 Hz),9.17(1H, s); mass spectrum (ESI): 396(M+H)

EXAMPLE 13 Preparation of3-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(3-trifluoromethylphenyl)-1H-pyrazole(1) Preparation of3,3-bis(methylthio)-1-(3-trifluoromethylphenyl)-2-propen-1-one

Potassium t-butoxide (6.56 g, 58.5 mmol) was added to tetrahydrofuransolution (60 mL) containing 3′-(trifluoromethyl)acetophenone (5.00 g,26.6 mmol) and carbon disulfide (3.52 mL, 58.5 mmol) at 0° C., and themixture was stirred at room temperature for 30 minutes under a nitrogenatmosphere. After that, iodomethane (8.27 mL, 133 mmol) was addedthereto, and the mixture was stirred at room temperature for 30 minutesunder a nitrogen atmosphere. After water was added thereto, the solutionwas extracted with ethyl acetate. The organic layer was washed withsaturated aqueous ammonium chloride solution and saturated brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The residue wasseparated and purified by a silica gel column chromatography (Biotage,Si+40M, hexane:ethyl acetate=7:1) to obtain the title compound (3.27 g,42%).

(2) Preparation of3-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(3-trifluoromethylphenyl)-1H-pyrazole

Triethylamine (0.10 mL, 0.72 mmol) was added to ethanol solution (5.0mL) of 3,3-bis(methylthio)-1-(3-trifluoromethylphenyl)-2-propen-1-one(200 mg, 0.68 mmol) and3-oxospiro[isobenzofuran-1(3H),4′-piperidine]monohydrate hydrochloride(177 mg, 0.69 mmol), and the mixture was stirred at 80° C. for 24 hoursunder a nitrogen atmosphere. After that, hydrazine monohydrate (0.083mL, 1.7 mmol) was added thereto, the mixture was stirred at 80° C. for 6hours. The reaction mixture was concentrated, and water was addedthereto, followed by extraction with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was separated and purified by asilica gel column chromatography (Biotage, Si+12M, hexane:ethylacetate=1:1) to obtain the title compound (86 mg, 30%).

¹HNMR (400MHz, CDCl₃, δppm): 1.75-1.84(2H, m), 2.31(2H, dt, J=13.2Hz,4.8 Hz), 3.38(2H, dt, J=12.8 Hz, 2.2 Hz), 3.76-3.84(2H, m), 6.07(1H, s),7.39(1H, d, J=7.3 Hz), 7.46-7.60(3H, m), 7.62-7.71(1H, m), 7.76 (1H, d,J=7.7 Hz), 7.83(1H, s), 7.90(1H, d, J=7.7 Hz); mass spectrum(ESI):414.1(M+H)

The following compounds were prepared according to a method similar tothe procedure of Example 13.

EXAMPLE 143-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyridin-4-yl)-1H-pyrazole

¹HNMR (400 MHz, DMSO-d₆, δppm): 1.70-1.82(2H, m), 2.30-2.45(2H, m),3.04-3.20(2H, m), 3.65-3.93(2H, m), 6.38-6.75(1H, m), 7.41-7.56(3H, m),7.58-7.70(2H, m), 7.74-7.80(2H, m), 7.84(1H, d, J=7.3 Hz), 8.14(1H, d,J=7.3 Hz), 8.26(1H, brs), 8.66(1H, brs); mass spectrum(ESI): 423.1(M+H)

EXAMPLE 153-(3-biphenylyl)-5-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.72-1.75(2H, m), 2.25-2.34(2H, m),3.35-3.41(2H, m), 3.82-4.13(2H, m), 6.10(1H, s), 7.32-7.67(11H, m),7.89(1H, s), 7.90(1H, d, J=7.3 Hz); mass spectrum (ESI): 422.2(M+H)

EXAMPLE 163-(3-bromophenyl)-5-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.74-1.84(2H, m), 2.32(2H, dt, J=13.3Hz,4.8 Hz), 3.39(2H, dt, J=12.7 Hz, 2.6 Hz), 3.75-3.86(2H, m), 6.05(1H, s),7.30(1H, d, J=7.9 Hz), 7.41(1H, d, J=7.6 Hz), 7.43-7.58(3H, m),7.64-7.77(2H, m), 7.91(1H, dd, J=7.6 Hz, 1.0 Hz); mass spectrum (ESI):424.1/426.1

EXAMPLE 173-(3-biphenylyl)-5-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-pyrazole

¹HNMR (400 MHz, DMSO-d₆, δppm): 1.80-1.95(2H, m), 2.38-2.52(2H, m),3.00-3.16(2H, m), 3.76-3.91(2H, m), 6.44(1H, s), 7.36-7.40(1H, m),7.43-7.56(3H, m), 7.57-7.78(4H, m), 7.83(1H, d, J=5.1 Hz), 8.01(1H, s),8.86(1H, d, J=5.1 Hz), 9.17(1H, s); mass spectrum (ESI): 423.1(M+H)

EXAMPLE 183-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyridin-4-yl)-1H-pyrazole

¹HNMR (400 MHz, DMSO-d₆, δppm): 1.82-1.96(2H, m), 2.39-2.55(2H, m),3.03-3.20(2H, m), 3.65-3.92(2H, m), 6.40-6.79(1H, m), 7.42-7.56(3 H, m),7.63(1H, brs), 7.84(1H, dd, J=5.1 Hz, 1.1 Hz), 8.14(2H, d, J=7.7 Hz),8.26(1H, brs), 8.66(1H, brs), 8.86(1H, d, J=4.8 Hz), 9.18(1H, s); massspectrum (ESI): 424.1(M+H)

EXAMPLE 193-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.78-1.88(2H, m), 2.35(2H, dt, J=4.4 Hz,13.2 Hz), 3.36-3.48(2H, m), 6.37(1H, s), 7.35-7.43(2H, m), 7.48-7.58(4H,m), 7.67(1H, t, J=7.3 Hz), 7.91(1H, d, J=7.7 Hz), 8.44-8.52(2H, m),8.83(1H, d, J=4.8 Hz); mass spectrum (ESI): 424

EXAMPLE 20 Preparation oftrans-3-(3-biphenylyl)-5-[3′-oxospiro[cyclohexane-1,1′(3H)-isobenzofuran]-4-yl]-1H-pyrazole(1) Preparation oftrans-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxylic acidimidazolide

To a solution oftrans-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran-4-carboxylic acid(1.00 g, 4.06 mmol) in tetrahydrofuran (25 mL) was addedN,N′-dicarbonyldiimidazole (858 mg, 4.47 mmol), and the mixture wasstirred at room temperature for 20 hours under a nitrogen atmosphere.The resulting solid was collected by filtration, washed withtetrahydrofuran, and dried to obtain the title compound (808 mg, 67%).

(2) Preparation oftrans-3-(3-biphenylyl)-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-1H-pyrazole

To a solution of 3′-phenylacetophenone (100 mg, 0.51 mmol) intetrahydrofuran (3.0 mL) was added 1.0M hexane solution (0.51 mL, 0.51mmol) containing lithiumhexamethyldisilazide at −78° C. After that, themixture was stirred at −78° C. for 5 minutes under a nitrogenatmosphere.Trans-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxylicacidimidazolide(151 mg, 0.51 mmol) was added thereto, and then the mixture was stirredat room temperature for 1.5 hours under a nitrogen atmosphere. Aftersaturated aqueous ammonium chloride solution was added thereto, thereaction solution was extracted with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was dissolved in ethanol (4.0 mL),and hydrazine monohydrate (0.037 mL, 1.5 mmol) was added thereto; themixture was stirred at room temperature for 15 hours. After the reactionsolution was concentrated in vacuo, the residue was separated andpurified by a silica gel column chromatography (Biotage, Si+25M,hexane:ethyl acetate=2:1 to 1:1) to give the title compound (132 mg,62%).

¹HNMR (400MHz, CDCl₃, δppm): 1.75-1.83(2H, m), 1.95-2.10(2H, m),2.14-2.23(2H, m), 2.25-2.38(2H, m), 3.10-3.18(1H, m), 6.56(1H, s),7.26-7.60(10H, m), 7.70(1H, d, J=7.3 Hz), 7.86(1H, d, J=7.3 Hz),7.98(1H, s); mass spectrum (ESI): 421.1(M+H)

The following compounds were prepared according to a method similar tothe procedure of Example 20.

EXAMPLE 21trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(2-phenylpyridin-4-yl)-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.81-1.93(2H, m), 1.98-2.10(2H, m),2.15-2.25(2H, m), 2.31-2.43(2H, m), 3.19-3.28(2H, m), 6.69(1H, s),7.35-7.53(5H, m), 7.56-7.63(2H, m), 7.89(1H, d, J=7.3 Hz), 7.96-8.05(2H,m), 8.12(1H, s), 8.72(1H, d, J=5.1 Hz); mass spectrum (ESI): 422.2(M+H)

EXAMPLE 22trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl-5-(1-phenylpyrazol-3-yl)-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.80-1.93(2H, m), 3.03-2.18(2H, m),2.19-2.30(2H, m), 2.31-2.42(2H, m), 6.61(1H, s), 6.79(1H, d, J=2.2 Hz),6.79(1H, d, J=2.2 Hz), 7.26-7.35(1H, m), 7.38-7.53(4H, m), 7.55-7.62(1H,m), 7.73(1H, d, J=8.8 Hz), 7.87(1H, d, J=7.7 Hz), 7.95(1H, d, J=2.2 Hz);mass spectrum (ESI): 411.2(M+H)

EXAMPLE 23trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.82-1.93(2H, m), 2.06-2.17(2H, m),2.20-2.32(2H, m), 2.33-2.42(2H, m), 3.21-3.26(1H, m), 6.91(1H, s),7.40(1H, d, J=7.7 Hz), 7.45-7.52(4H, m), 7.55-7.60(2H, m), 7.85-7.89(1H,m), 8.46-8.51(2H, m), 8.82(1H, d, J=5.1 Hz); mass spectrum (ESI):423.1(M+H)

EXAMPLE 24trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(6-phenylpyrazin-2-yl)-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.86-1.92(2H, m), 2.10-2.18(2H, m),2.23-2.31(2H, m), 2.36-2.44(2H, m), 3.23-3.30(1H, m), 6.88(1H, s),7.43(1H, d, J=7.7 Hz), 7.47-7.62(5H, m), 7.88(1H, d, J=7.7 Hz),8.06-7.10(2H, m), 8.95(1H, s), 8.97(1H, s); mass spectrum (ESI):423.1(M+H)

EXAMPLE 25trans-3-(3-chlorophenyl)-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.80-1.94(2H, m), 1.98-2.12(2H, m),2.13-2.28(2H, m), 2.30-2.47(2H, m), 3.16-3.28(1H, m), 6.53(1H, s),7.25-7.43(3H, m), 7.46-7.68(3H, m), 7.76(1H, s), 7.90(1H, d, J=7.5 Hz);mass spectrum (ESI): 379.1/381.1(M+H)

EXAMPLE 26trans-3-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(2-quinolyl)-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.83-1.94(2H, m), 2.10-2.21(2H, m),2.24-2.44(4H, m), 3.22-3.30(1H, m), 6.85(1H, s), 7.42-7.62(4H, m),7.70-7.76(1H, m), 7.80-7.90(3H, m), 8.10(1H, d, J=8.4 Hz), 8.21(1H, d,J=8.4 Hz); mass spectrum (ESI): 396.0(M+H)

EXAMPLE 27trans-3-(3-biphenylyl)-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.78-1.88(2H, m), 1.90-2.03(2H, m),2.05-2.31(4H, m), 3.01-3.14(1H, m), 6.54(1H, s), 7.26-7.45(4H, m),7.46-7.56(3H, m), 7.60-7.78(2H, m), 7.92(1H, s), 8.78(1H, d, J=5.1 Hz),8.82(1H, s); mass spectrum (ESI): 422.2(M+H)

EXAMPLE 28trans-3-(3-biphenylyl)-5-[3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.85-1.97(2H, m), 2.06-2.17(2H, m),2.18-2.38(2H, m), 2.34-2.43(2H, m), 3.20-3.28(1H, m), 6.55(1H, s),7.35-7.55(5H, m), 7.58-7.70(4H, m), 7.79(1H, s), 8.78(1H, d, J=5.1 Hz),9.15(1H, d, J=1.1 Hz); mass spectrum (ESI): 422.2(M+H)

EXAMPLE 29trans-3-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole

¹HNMR (400 MHz, CDCl₃, δppm): 1.92-2.05(2H, m), 2.16-2.31(4H, m)2.35-2.45(2H, m), 3.21-3.30(1H, m), 6.88(1H, s), 7.49-7.55(4H, m),7.76-7.79(1H, m), 8.47-8.53(2H, m), 8.85(2H, d, J=5.1 Hz), 8.95(1H, s);mass spectrum (ESI): 424.1(M+H)

EXAMPLE 303-(2-naphthyl)-5-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-1,2,4-triazole(1) Preparation of[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]carbonitrile

To a solution of spiro[isobenzofuran-1(3H),4′-piperidin]-3-onehydrochloride monohydrate (1.50 g, 6.26 mmol) in N,N-dimethylformamide(30 mL) were added cyanogen bromide (800 mg, 7.22 mmol) andtriethylamine (1.92 mL, 13.8 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate and washed with water and saturated brine. The organiclayer was dried over anhydrous sodium sulfate, and concentrated in vacuoto obtain the title compound (1.32 g, 92%) as a colorless solid.

(2) Preparation of3-(2-naphthyl)-5-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-1H-1,2,4-triazole

Ytterbium triflate (30 mg, 0.043 mmol) was added to toluene solution(0.5 mL) containing 2-naphthalenecarboxylic acid hydrazide (30 mg, 0.16mmol) and[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]carbonitrile (30 mg,0.13 mmol), and the mixture was stirred at 140° C. for 11 hours in asealed tube. After saturated aqueous sodium bicarbonate solution wasadded to the reaction solution, the solution was extracted withethylacetate. The organic layer was dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was separated and purified by asilica gel column chromatography (Biotage 12M, chloroform:methanol=40:1)to obtain the title compound (20 mg, 38%) as a colorless solid.

¹HNMR (400 MHz, DMSO-d₆, δppm): 1.60-1.86(2H, m), 2.22-2.68(2H, m),3.12-3.60(2H, m), 4.02-4.22(2H, m), 7.42-8.20(11H, m); mass spectrum(ESI): 397(M+H)

The following compounds were prepared according to a method similar tothe procedure of Example 30.

EXAMPLE 313-[3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(3-trifluoromethylphenyl)-1H-1,2,4-triazole

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.67-1.82(2H, m), 2.25-2.43(2H, m),3.14-3.45(2H, m), 4.05-4.20(2H, m), 7.59-7.93(6H, m), 8.15-8.30(2H, m),12.94(0.85H, s), 13.83(0.15H, s); mass spectrum (ESI): 415(M+H)

EXAMPLE 32 Preparation oftrans-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazoleandcis-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole(1) Preparation of 1,5-diamino-3-(4-fluorophenyl)-1H-pyrazole

Hydroxylamine-O-sulfonic acid (2.26 g, 20.0 mmol) was portionwise addedto aqueous solution (100 mL) containing5-amino-3-(4-fluorophenyl)-1H-pyrazole (2.0 g, 11.3 mmol) and potassiumhydroxide (2.52 g, 45 mmol) while stirring at 80° C. After the mixturewas stirred at 80° C. for 30 minutes, potassium hydroxide (2.52 g, 45mmol) was added thereto, hydroxylamine-O-sulfonic acid (2.26 g, 20.0mmol) was portionwise added, and the mixture was stirred for further 1hour. The reaction solution was cooled down to room temperature, andextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous potassium carbonate, andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (C-300, hexane:ethyl acetate=1:2) to obtain the titlecompound (324 mg, 14.9%).

(2) Preparation oftrans-N-[1-amino-3-(4-fluorophenyl)-1H-pyrazol-5-yl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamideandtrans-N-[5-amino-3-(4-fluorophenyl)-1H-pyrazol-1-yl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

3-Ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg,1.17 mmol) was added to pyridine solution (2 mL) containingtrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid(247 mg, 1.0 mmol) and 1,5-diamino-3-(4-fluorophenyl)-1H-pyrazole (192mg, 1.0 mmol), and the mixture was stirred overnight at room temperatureunder a nitrogen atmosphere. The reaction solution was diluted withethyl acetate, and washed with water and saturated brine. The organiclayer was dried over anhydrous magnesium sulfate and concentrated invacuo. The residue was separated and purified by a silica gel columnchromatography (C-300, methanol:chloroform=1:50 to 1:20) to obtain thetitle compounds (137 mg, 32.6% and 107 mg, 25.5%, respectively).

(3) Preparation oftrans-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan1-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazoleandcis-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole

Trans-N-[5-amino-3-(4-fluorophenyl)-1H-pyrazol-1-yl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-carboxamide(101 mg, 0.24 mmol) was suspended in phosphorous oxychloride (1 mL), andthe suspension was stirred overnight at 100° C. The reaction solutionwas cooled down to room temperature and poured portionwise into water.After the solution was adjusted to pH 7 with saturated aqueous sodiumbicarbonate solution, it was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The residue was separated andpurified by silica gel column chromatography (C-300,methanol:chloroform=1:100 to 1:10, and C-300, hexane:ethyl acetate=2:1to ethyl acetate alone) to obtain the title compound (18.3 mg, 18.9% and7.4 mg, 7.6%, respectively) as a white solid.

Trans form:

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.9-2.1(2H, m), 2.1-2.3(6H, m),3.2-3.4(1H, m), 6.32(1H, s), 7.23(2H, t, J=8.9 Hz), 7.8-7.9(3H, m),8.88(1H, d, J=5.0 Hz), 9.23(1H, s), 12.74(1H, s); mass spectrum (ESI):404(M+H)

Cis form:

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.84-1.95(2H, m), 1.96-2.09(2H, m),2.1-2.2(2H, m), 2.29-2.43(2H, m), 3.05-3.18(1H, m), 6.27(1H, s),7.21(2H, t, J=8.9 Hz), 7.8-7.9(3H, m), 8.88(1H, d, J=5.0 Hz), 9.16(1H,s), 12.75(1H,brs); mass spectrum (ESI): 404(M+H)

EXAMPLE 33 Preparation oftrans-6-(3-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazoleandcis-6-(3-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b[1,2,4]triazole

The title compounds were prepared according to a method similar to theprocedure of Example 32(3), usingtrans-N-[1-amino-3-(3-fluorophenyl)-1H-pyrazol-5-yl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamidewhich had been synthesized according to a method similar to the methodof Examples 32(1) and 32(2).

Trans form:

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.95-2.05(2H, m), 2.1-2.4(6H, m),3.2-3.4(1H, m), 6.42(1H, s), 7.05-7.15(1H, m), 7.4-7.5(1H, m),7.6-7.7(1H, m), 7.71(1H, d, J=7.7 Hz), 7.85(1H, d, J=5.0 Hz), 8.88(1H,d, J=5.0 Hz), 9.23(1H, s), 12.80(1H, brs); mass spectrum (ESI): 404(M+H)

Cis form:

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.84-1.96(2H, m), 1.96-2.09(2H, m),2.1-2.2(2H, m), 2.29-2.43(2H, m), 3.05-3.18(1H, m), 6.38(1H, s),7.05-7.15(1H, m), 7.38-7.48(1H, m), 7.58-7.65(1H, m), 7.69(1H, d, J=7.9Hz), 7.84(1H, d, J=5.0 Hz), 8.88(1H, d, J=5.0 Hz), 9.16(1H, s), 12.8(1H, brs); mass spectrum (ESI): 404(M+H)

The following compounds were prepared according to a method similar tothe method of Example 32 or 33.

EXAMPLE 34trans-6-(2-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.95-2.05(2H, m), 2.1-2.4(6H, m),3.2-3.4(1H, m), 6.21(1H, d, J=3.9 Hz), 7.2-7.4(3H, m), 7.86(1H, d, J=5.1Hz), 7.9-8.1(1H, m), 8.88(1H, d, J=5.1 Hz), 9.23(1H, s), 12.8(1H, br s);mass spectrum (ESI): 404(M+H)

EXAMPLE 35trans-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.95-2.05(2H, m), 2.1-2.4(6H, m),3.2-3.4(1H, m), 6.32(1H, s), 7.25-7.35(1H, m), 7.35-7.45(2H, m),7.8-7.9(3H, m), 8.88(1H, d, J=5.0 Hz), 9.23(1H, s), 12.7(1H, brs); massspectrum (ESI): 386(M+H)

EXAMPLE 36trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.75-1.95(2H, m), 2.1-2.4(6H, m),3.2-3.4(1H, m), 6.31(1H, s), 7.25-7.35(1H, m), 7.35-7.45(2H, m),7.55-7.65(1H, m), 7.7-7.8(2H, m), 7.8-7.9(3H, m), 12.7(1H, brs); massspectrum (ESI): 385(M+H)

EXAMPLE 37cis-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.75-1.85(2H, m), 1.96-2.2(4H, m),2.2-2.4(2H, m), 3.0-3.2(1H, m), 6.27(1H, s), 7.2-7.3(1H, m), 7.3-7.4(2H, m), 7.55-7.65(1H, m), 7.7-7.9(5H, m), 12.7(1H, brs); mass spectrum(ESI): 385(M+H)

EXAMPLE 38trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-phenyl-1H-imidazo[1,2-b][1,2,4]triazole

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.7-1.8(2H, m), 2.1-2.4(6H, m),3.15-3.25(1H, m), 7.29-7.37(1H, m), 7.4-7.5(2H, m), 7.55-7.65(2H, m),7.7-7.8(3H, m), 7.80-7.86(3H, m), 8.16(1H, s), 12.3(1H, brs); massspectrum (ESI): 385(M+H)

EXAMPLE 39trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-phenyl-1H-[1,2,4]triazolo[2,3-b][1,2,4]triazole

¹HNMR (300 MHz, DMSO-d₆, ppm): 1.6-1.85(2H, m), 2.1-2.4(6H, m),3.1-3.8(1H, m), 7.3-7.4(1H, m), 7.4-7.5(2H, m), 7.55-7.63(1H, m),7.64-7.7(1H, m), 7.70-7.78(1H, m), 7.8-7.86(1H, m), 7.88-8.06(2H, m),13.2 (1H, brs); mass spectrum (ESI): 386(M+H)

EXAMPLE 40trans-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2-phenyl-2,4-dihydroimidazo[4,5-d][1,2,3]triazole

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.74-1.86(2H, m), 2.14-2.40(6H, m),3.14-3.24(1H, m), 7.36(1H, t, J=7.5 Hz), 7.52-7.64(3H, m), 7.66-7.79(2H, m), 7.52(1H, d, J=7.5 Hz), 8.03(2H, d, J=8.2 Hz), 12.68(1H, brs);mass spectrum (ESI): 386(M+H)

EXAMPLE 41trans-2-(2-fluorophenyl)-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2,4-dihydroimidazo[4,5-d][1,2,3]triazole

4,5-Diamino-2-(2-fluorophenyl)-2H-[1,2,3]triazole was synthesizedaccording to a method similar to the procedure described in Andrianov,V. G.; Semenikhina, V. G.; Eremeev, A. V.; Chem. Heterocycl. Compd.,vol. 28, pages 803-807 (1992).

¹HNMR (300 MHz, CD₃OD/CDCl₃=4/1, δppm): 1.86-1.97(2H, m), 2.20-2.48 (6H,m), 3.38-3.46(1H, m), 7.31-7.90(8H, m); mass spectrum (ESI): 404(M+H)

EXAMPLE 42trans-2-(4-fluorophenyl)-5-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2,4-dihydroimidazo[4,5-d][1,2,3]triazole

4,5-Diamino-2-(4-fluorophenyl)-2H-[1,2,3]triazole was synthesizedaccording to a method similar to the procedure of Example 40.

¹HNMR (300 MHz, CD₃OD/CDCl₃=4/1, δppm): 1.86-1.98(2H, m), 2.20-2.45(6H,m), 3.35-3.45(1H, m), 7.23(2H, t, J=8.9 Hz), 7.55-7.63(1H, m),7.65-7.74(2H, m), 7.85-7.90(1H, m), 8.09(2H, dd, J=4.7 Hz, 8.9 Hz); massspectrum (ESI): 404(M+H)

EXAMPLE 43trans-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazole(1) Preparation of methyl 4-nitro-1H-pyrazole-3-carboxylate

Thionyl chloride (5.1 mL, 70.0 mmol) was added portionwise to a solutionof 4-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.7 mmol) inmethanol(100 mL). After the mixture was stirred overnight at room temperature,the solvent was evaporated in vacuo. After the residue was dissolved inethyl acetate, the solution was washed with water and saturated aqueousbrine, dried over anhydrous magnesium sulfate, and concentrated in vacuoto obtain the title compound (10.43 g, 95.8%).

(2) Preparation of methyl 4-nitro-1-phenyl-1H-pyrazole-3-carboxylate

To a solution of 4-nitro-1H-pyrazole-3-carboxylate (1.0 g, 5.84 mmol)inmethylene chloride (20 mL) were added phenylboric acid (1.43 g, 11.7mmol), copper(II) acetate (1.60 g, 8.76 mmol) and pyridine (2 mL, 23.4mmol), and the mixture was stirred overnight at room temperature underan air atmosphere. After removal of the insolubles by filtration, thefiltrate was washed with water (twice) and saturated brine, dried overanhydrous magnesium sulfate and concentrated in vacuo to obtain thetitle compound (1.21 g, 83.5%).

(3) Preparation of 4-nitro-1-phenyl-1H-pyrazole-3-carboxylic acid

Methyl 4-nitro-1-phenyl-1H-pyrazole-3-carboxylate (1.14 g, 4.63 mmol)was suspended in 1N sodium hydroxide (11 mL), and the solution wasstirred at room temperature for 2 hours under a nitrogen atmosphere. Theprecipitates formed upon addition of IN hydrochloric acid (12 mL) werecollected by filtration, washed with water and dried to obtain the titlecompound (1.00 g, 93.2%).

(4) Preparation of 3-amino-4-nitro-1-phenyl-1H-pyrazole

To a solution of 4-nitro-1-phenyl-1H-pyrazole-3-carboxylic acid (1.00 g,4.29 mmol) in 1,4-dioxane (15 mL) were added diphenylphosphoryl azide(1.44 mL, 6.65 mmol), triethylamine (1.79 mL, 12.9 mmol) and2-methyl-2-propanol (7.2 mL, 75.3 mmol), and the mixture was heatedunder reflux for 2 hours under a nitrogen atmosphere. The reactionsolution was cooled down to room temperature, and ethyl acetate wasadded thereto. The mixture was washed successively with water, saturatedaqueous sodium bicarbonate solution and saturated brine, dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingresidue was dissolved in chloroform (10 mL), and then trifluoroaceticacid (5 mL) was added thereto. The solution was stirred at roomtemperature for 1 hour under a nitrogen atmosphere. After the reactionsolution was concentrated, ethyl acetate was added to the resultingresidue. The solutionwas washedwith saturatedaqueous sodiumbicarbonatesolution and saturated aqueous brine, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. Diisopropyl ether was added to theresulting residue, and the precipitates were collected by filtration anddried to obtain the title compound (827 mg, 94%).

(5) Preparation of 3,4-diamino-1-phenyl-1H-pyrazole

To a solution of 3-amino-4-nitro-1-phenyl-1H-pyrazole (200 mg, 0.98mmol) in methanol (30 mL) were added conc. hydrochloric acid (0.5 mL)and 10% palladium-carbon (20 mg), and the mixture was stirred for 1.5hours at room temperature under a hydrogen atmosphere. After removal ofthe catalyst by filtration, the filtrate was concentrated, and aqueoussodium bicarbonate solution was added to the resulting residue. Thesolution was extracted 5 times with chloroform, and the chloroform layerwas dried over anhydrous magnesium sulfate, and then concentrated invacuo. Diisopropyl ether was added to the resulting residue, and theprecipitates were collected by filtration and dried to obtain the titlecompound (101 mg, 58.6%).

(6) Preparation oftrans-N-(4-mino-1-phenyl-1H-pyrazol-3-yl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

To a solution oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (100 mg, 0.404 mmol) and 3,4-diamino-1-phenyl-1H-pyrazole (70 mg,0.404 mmol) in pyridine (2 mL) was added3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride (90 mg, 0.53mmol), and the mixture was stirred overnight at room temperature under anitrogen atmosphere. The reaction solution was diluted with ethylacetate, and washed with water and saturated brine. The organic layerwas dried over anhydrous magnesium sulfate and concentrated in vacuo.Diisopropyl ether was added to the resulting residue, and theprecipitates were collected by filtration and dried to obtain the titlecompound (121 mg, 74.2%).

(7) Preparation oftrans-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenyl-2,4-dihydroimidazo[4.5-c]pyrazole

Trans-N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide(121 mg, 0.30 mmol) was suspended in phosphorous oxychloride (1 mL), andthe suspension was stirred at 120° C. for 2 hours. The reaction solutionwas cooled down to room temperature, and then poured into waterportionwise. The solution was adjusted to pH 6 using 5N sodium hydroxideaqueous solution, and then extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium bicarbonate solution andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated in vacuo. The residue was separated and purified by asilica gel column chromatography (C-300, methanol:chloroform=1:100 to1:20) to obtain the title compound (4.5 mg, 3.9%) as a white solid.

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.9-2.1(2H, m), 2.1-2.4(6H, m),3.2-3.4(1H, m), 7.25(1H, t, J=6.8 Hz ), 7.44-7.52(2H, m), 7.84-7.92(3H,m), 8.36(1H, brs), 8.89(1H, d, J=5.1 Hz), 9.18(1H, s), 11.8(1H, s) massspectrum (ESI): 386(M+H)

EXAMPLE 44 Preparation oftrans-6-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenyl-1H-imidazo[1,2-b]pyrazole(1)Preparationofmethyltrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylate

1-(3-Diimethylaminopropyl)-3-ethylcarbodilmide hydrochloride (220 mg,1.17 mmol) was added to pyridine solution (4 mL) containingtrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (500 mg, 2.02 mmol) and methanol (1 mL), and the mixture wasstirred at room temperature for 20 hours under a nitrogen atmosphere.After addition of ethyl acetate, the reaction solution was washedsuccessively with water, 10% citric acid solution, saturated aqueoussodium bicarbonate solution and saturated brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo to remove the solvent,thereby to obtain the title compound (521.4 mg, 98.7%).

(2) Preparation oftrans-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-3-oxo-3-propionitrile

2.66 M n-butyl lithium/hexane solution (1.125 mL, 2.99 mmol) was addedto tetrahydrofuran (10 mL) at −78° C. and subsequently acetonitrile (0.2mL) was added at -78° C.; the mixture was stirred for 30 minutes. Methyltrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylate(521 mg, 1.99 mmol) was added thereto, and the mixture was stirred for 2hours while gradually raising the temperature from −78° C. to roomtemperature. After addition of 10% citric acid solution, the reactionsolution was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium bicarbonate solution and saturated brine,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (C-300,hexane:ethyl acetate=1:2 to 4:1) to obtain the title compound (210 mg,39%).

(3) Preparation of3-amino-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole

Aftertrans-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-3-oxo-3-propionitrile(210 mg) was dissolved in ethanol (8 mL), hydrazine monohydrate (0.045mL, 0.93 mmol) was added thereto, and the solution was stirred at refluxfor 4 hours. Hydrazinemonohydrate (0.045 mL, 0.93 mmol) was furtheradded thereto, and the solution was stirred at ref lux for 2 hours. Thesolution was adjusted to pH 2 using conc. hydrochloric acid, and stirredfor one hour. After saturated aqueous sodium bicarbonate solution wasadded to the solution to adjust the pH to 8, it was extracted with ethylacetate four times. The extract was dried over anhydrous magnesiumsulfate and concentrated in vacuo to obtain the title compound (184 mg,83%) as a cis and trans mixture (2:3).

(4) Preparation of3-amino-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenacyl-2H-pyrazole

3-Amino-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1-cyclohexan]-4′-yl]-1H-pyrazole(180 mg, 0.633 mmol), phenacyl chloride (150 mg, 0.94 mmol) andpotassium carbonate (180 mg, 1.27 mmol) were stirred overnight at roomtemperature in N,N-dimethylformamide (10 mL). The mixture was stirredfor further 1 hour at 80° C. The reaction solution was cooled down toroom temperature and ethyl acetate was added thereto. The reactionsolution was washed with water and saturated brine, and the organiclayer was dried over anhydrous magnesium sulfate and concentrated invacuo to remove the solvent. The residue was separated and purified by asilica gel column chromatography (C-300, methanol:chloroform=1:50 to1:30) to obtain the title compound (26.5 mg, 10.4%) as a cis and transmixture.

(5) Preparation oftrans-6-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenyl-1H-imidazo[1,2-b]pyrazole

A solution of3-amino-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenacyl-2H-pyrazole(26.5 mg, 0.058 mmol) in ethanol (0.5 mL) was refluxed overnight. Thesolvent was evaporated in vacuo, and the residue was separated andpurified by a silica gel column chromatography (C-300, ethylacetate:hexane=1:1 to 2:1 andmethanol:chloroform=1:50) to obtain thetitle compound (2.3 mg, 10.3%).

¹HNMR (300 MHz, DMSO-d₆, δppm): 1.8-2.3(8H, m), 3.0-3.4(1H, m), 5.72(1H, s), 7.2-7.8(5H, m), 7.86(1H, dd, J=1.1 Hz, 4.9 Hz), 8.06(1H, s),8.87 (1H, d, J=4.9 Hz), 9.08(1H, d, J=1.1 Hz), 11.4(1H, brs); massspectrum (ESI): 385(M+H)

The following compounds were synthesized according to a method similarto the procedure of Example 13.

EXAMPLE 453-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole

¹HNMR (400 MHz, DMSO-d6, δppm): 1.82-1.94(2H, m), 2.39-2.57(2H, m),3.05-3.20(2H, m), 3.78-3.85(2H, m), 6.78(1H, s), 7.48-7.58(3H, m),7.67-7.77(1H, m), 7.84(1H, dd, J=1.1 Hz, 5.1 Hz), 8.50-8.64(2H, m),8.84-8.95(1H, m), 8.86(1H, d, J=5.1 Hz), 9.18(1H, s); mass spectrum(ESI): 425

EXAMPLE 463-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-[2-(2-fluorophenyl)pyrimidin-4-yl]-1H-pyrazole

¹HNMR (400 MHz, DMSO-d6, δppm): 1.80-1.94(2H, m), 2.39-2.57(2H, m),3.05-3.20(2H, m), 3.70-3.95(2H, m), 6.65(1H, s), 7.20-7.36(2H, m),7.45-7.55(1H, m), 7.65-7.80(1H, m), 7.78(1H, d, J=5.lHz), 8.20(1H, s)8.83(1H, d, J=5.1 Hz), 8.83-8.95(1H, m), 9.12(1H, s); mass spectrum(ESI): 443

EXAMPLE 473-[3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-yl]-5-[2-(4-fluorophenyl)pyrimidin-4-yl]-1H-pyrazole

¹HNMR (400 MHz, DMSO-d6, δppm): 1.83-1.95(2H, m), 2.39-2.60(2H, m),3.05-3.20(2H, m), 3.70-3.95(2H, m), 6.77(1H, s), 7.30-7.39(2H, m),7.65-7.85(2H, m), 8.50-8.70(2H, m), 8.80-8.94(2H, m), 9.18(1H, s); massspectrum (ESI): 443

Formulation Example 1

The compound (20.0 g) of Example 1, lactose (417 g), crystallinecellulose (80 g) and partial a-starch (80 g) were blended using a V coneblender. To the mixture was added magnesium stearate (3.0 g), and thewhole was blended. The blended powder was compressed into 3,000 tabletsby conventional procedure so that each tablet has a diameter of 7.0 mmand a weight of 150 mg.

Content per tablet (150 mg)

The Compound of Example 1 5.0 mg Lactose 104.25 mg Crystalline cellulose20.0 mg Partial α-starch 20.0 mg Magnesium stearate 0.75 mg

Formulation Example 2

Hydroxypropyl cellulose 2910 (10.8 g) and polyethylene glycol 6000 (2.1g) were dissolved in purified water (172.5 g). To the solution wasdispersed titanium dioxide (2.1 g) to provide a coating liquid. 2,500tablets separately prepared according to Formulation Example 1 weresubjected to spray-coating with the coating liquid using HICOATER-MINIto provide film coated tablets with a weight of 155 mg.

Content per tablet (155 mg)

The tablets of Formulation Example 1 150 mg Hydroxypropyl cellulose 29103.6 mg Polyethylene glycol 6000 0.7 mg Titanium dioxide 0.7 mg

INDUSTRIAL APPLICABILITY

Since compounds of the present invention exhibit NPY antagonisticeffects especially on NPY Y5 receptors and show excellentpharmacokinetics such as transport into brain or transport tocerebrospinal fluid, etc., and they are highly safe, they are useful forthe treatment of various diseases related to NPY, for example,cardiovascular disorders such as angina, acute or congestive heartfailure, myocardial infarction, hypertension, nephropathy, electrolyteabnormality, vasospasm, atherosclerosis, etc., central nervous systemdisorders such as bulimia, depression, anxiety, seizure, epilepsy,dementia, pain, alcoholism, drug withdrawal, circadian rhythm disorders,schizophrenia, memory impairment, sleep disorders, cognitive impairment,etc., metabolic diseases such as obesity, diabetes, hormone abnormality,hypercholesterolemia, hyperlipemia, gout, fatty liver, etc., genital orreproductive disorders such as infertility, preterm labor, sexualdysfunction, etc., gastrointestinal disorders, respiratory disorder,inflammatory diseases or glaucoma, and the like, also for example,atherosclerosis, hypogonadism, hyperandrogenism, polycystic ovarysyndrome, hirsutism, gastro-intestinal motility disorder,obesity-related gastro-esophageal reflux, obesity hypoventilation(Pickwickian syndrome), sleep apnea, inflammation, systemic inflammationof the vasculature, osteoarthritis, insulin resistance,bronchoconstriction, alcohol preference, metabolic syndrome, (syndromeX), Alzheimer's disease, cardiac hypertrophy, left ventricularhypertrophy, hypertriglyceridemia, low HDL cholesterol, cardiovasculardisorders such as coronary heart disease (CHD), cerebrovascular disease,stroke, peripheral vascular disease, sudden death, gallbladder diseases,cancer (breast, endometrial, colon), breathlessness, hyperuricemia,impaired fertility, low back pain, or increased anesthetic risk, and thelike; renal system diseases; renal abnormalities such as dysfunction inbody fluid flow, abnormalities of material transportation, andrenalfailure; shock; arrhythmia; symptoms related to surge in sympathomimeticactivity during or after operation on coronary artery orgastrointestinal tracts; diseases related to brain or central nervoussystem, such as cerebral infarction, neurodegeneration, cerebral stroke,cerebrovascular spasm or cerebral hemorrhage; symptoms related to painor nociception; diseases related to abnormalities in gastrointestinalmotility or secretion, such as various ileuses, urinary incontinence,and Crohn's disease; eating disorders such as anorexia and bulimia;inflammatory symptoms or diseases; asthma; bronchiole constriction; ordiseases related to abnormal secretion of hormones such asluteinizinghormone, growth hormone, insulin, and luteotropic hormone.

1. A compound of the formula (I):

wherein Az is a group comprising a monocyclic azole or a bicyclicaromatic ring of the same or different fused azoles, which is optionallysubstituted by a substituent selected from the group consisting ofhalogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, loweralkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹; Ar¹ is aryl or heteroaryl, anyof which is optionally substituted by a substituent selected from thegroup consisting of halogen, nitro, oxo, hydroxy, lower alkyl,halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl,lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and-Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionallysubstituted by a substituent selected from the group consisting ofhalogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl,hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-loweralkylamino, lower alkanoyl and aryl; Q¹ and Q² are independently asingle bond, oxygen atom, carbonyl or —N(R³)—; R¹ and R² areindependently hydrogen atom or lower alkyl, or R¹ and R², takentogether, form lower alkylene which may be interrupted by oxygen atom,sulfur atom or imino; R³ is hydrogen atom or lower alkyl; T, V and W areindependently methine, U is nitrogen atom, said methine being optionallysubstituted by a substituent selected from the group consisting ofhalogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy andhalo-lower alkoxy; and X is methine, or a salt or ester thereof.
 2. Thecompound, or a salt or ester thereof, as claimed in claim 1, wherein Azis a group comprising a monocyclic azole or a bicyclic aromatic ring ofthe same or different fused azoles, which is substituted by -Q¹-Ar¹. 3.The compound, or a salt or ester thereof, as claimed in claim 1, whereina group comprising a monocyclic azole as Az is selected from thefollowing formulae (a):


4. The compound, or a salt or ester thereof, as claimed in claim 1,wherein a group comprising a bicyclic aromatic ring of the same ordifferent fused azoles as Az is selected from the following formulae(b):


5. The compound, or a salt or ester thereof, as claimed in claim 1,wherein Q¹ is a single bond.
 6. The compound, or a salt or esterthereof, as claimed in claim 1, wherein Ar¹ is phenyl or naphthyl, anyof which is optionally substituted by a substituent selected from thegroup consisting of halogen, nitro, oxo, hydroxy, lower alkyl,halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl,lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower. alkanoylamino and-Q²-Ar².
 7. The compound, or a salt or ester thereof, as claimed inclaim 1, wherein Ar¹ is heteroaryl which is optionally substituted by asubstituent selected from the group consisting of halogen, nitro, oxo,hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-loweralkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio,lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl,lower alkanoylamino and -Q²-Ar².
 8. The compound, or a salt or esterthereof, as claimed in claim 7, wherein the heteroaryl is imidazolyl,furyl, thienyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl,oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,benzofuranyl, quinolyl or isoquinolyl.
 9. The compound, or a salt orester thereof, as claimed in claim 1, wherein Az is a group selectedfrom the following formulae (a₁):

wherein Y is hydrogen atom, halogen, cyano, lower alkyl, halo-loweralkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl,lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² or -Q¹-Ar¹; Ar¹ isaryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, nitro, oxo,hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-loweralkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio,lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl,lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of whichis optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, loweralkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q¹ and Q² areindependently a single bond, oxygen atom, carbonyl or —N(R³)—; R¹ and R²are independently hydrogen atom or lower alkyl, or R¹ and R², takentogether, form lower alkylene which may be interrupted by oxygen atom,sulfur atom or imino; and R³ is hydrogen atom or lower alkyl, or thefollowing formulae (b₁):

 wherein Y has the same meaning as defined above.
 10. The compound, or asalt or ester thereof, as claimed in claim 9, wherein Y is -Q¹-Ar¹. 11.The compound, or a salt thereof, as claimed in claim 1, which istrans-2-(2-naphthyl)-4′-[3-oxospiro[6-azaisobenzofuran-1(3H),1-cyclohexan]-4′-yl]-1H-imidazole,trans-3-(3-biphenylyl)-5-[3-oxospiro[6-azaisobenzofuran1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole,trans-3-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole,trans-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,cis-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,trans-6-(3-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,cis-6-(3-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,trans-6-(2-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole,trans-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole,trans-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazole,ortrans-6-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenyl-1H-imidazo[1,2-b]pyrazole.12. The compound, or a salt thereof, as claimed in claim 1, which istrans-3-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-5-(2-phenylpyrimidin-4-yl)-1H-pyrazole.13. The compound, or a salt thereof, as claimed in claim 1, which istrans-6-(2-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazolo[2,3-b][1,2,4]triazole.14. The compound, or a salt thereof, as claimed in claim 1, which istrans-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-6-phenyl-1H-pyrazolo[2,3-b][1,2,4]triazole.15. A process for preparing a compound of the formula (I-1):

wherein Ar¹ is aryl or heteroaryl, any of which is optionallysubstituted by a substituent selected from the group consisting ofhalogen, nitro, oxo, hydroxy, lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy,halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² isaryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, cyano, loweralkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl; Q¹ and Q² are independently a single bond, oxygen atom,carbonyl or —N(R³)—; R¹ and R² are independently hydrogen atom or loweralkyl, or R¹ and R², taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or imino; and R³ is hydrogenatom or lower alkyl; T, V and W are independently methine, U is nitrogenatom, said methine being optionally substituted by a substituentselected from the group consisting of halogen, lower alkyl, halo-loweralkyl, hydroxy, lower alkoxy and halo-lower alkoxy; and X is methine;and Y and Z are independently hydrogen atom, halogen, cyano, loweralkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, loweralkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² or-Q¹-Ar¹, or a salt or ester thereof, by reacting a compound of theformula (II):

 where in L¹ is a leaving group; y and z are independently hydrogenatom, halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy,halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, loweralkylsulfonyloxy, —N(R^(1P))R^(2P), -Q^(1P)-Ar^(1P) or optionallyprotected hydroxy; Ar^(1P) is aryl or heteroaryl, any of which isoptionally substituted by a substituent selected from the groupconsisting of halogen, nitro, lower alkyl, halo-lower alkyl, cyclo-loweralkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio,lower alkylsulfonyl, lower alkanoyl, lower alkoxycarbonyl, loweralkanoylamino, -Q^(2P)-Ar^(2P), optionally protected oxo, optionallyprotected hydroxy, optionally protected hydroxy-lower alkyl andoptionally protected carboxyl; Ar^(2P) is aryl or heteroaryl, any ofwhich is optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy, di-lower alkylamino, lower alkanoyl, aryl,optionally protected hydroxy-lower alkyl, optionally protected hydroxyand optionally protected lower alkylamino; Q^(1P) and Q^(2P) areindependently a single bond, oxygen atom, optionally protected carbonylor —N(R³)—; R^(1P) and R^(2P) are independently an amino-protectinggroup, an imino-protecting group, hydrogen atom or lower alkyl, orR^(1P) and R^(2P), taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or optionally protected imino;and R³ has the same meaning as defined above, with a compound of theformula (III):

 wherein t, v and w are independently methine, u is nitrogen atom, saidmethine being optionally substituted by a substituent selected from thegroup consisting of halogen, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy and optionally protected hydroxy; and X hasthe same meaning as defined above or its salt to give a compound of theformula (IV):

 wherein t, u, v, w, X, y and z have each the same meaning as definedabove, and optionally removing the protecting group(s) therefrom.
 16. Aprocess for preparing a compound of the formula (I-2):

wherein Ar¹ is aryl or heteroaryl, any of which is optionallysubstituted by a substituent selected from the group consisting ofhalogen, nitro, oxo, hydroxy, lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy,halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² isaryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, cyano, loweralkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl; Q¹ and Q² are independently a single bond, oxygen atom,carbonyl or —N(R³)—; R¹ and R² are independently hydrogen atom or loweralkyl, or R¹ and R², taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or imino; T, V and W areindependently methine, U is nitrogen atom, said methine being optionallysubstituted by a substituent selected from the group consisting ofhalogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy andhalo-lower alkoxy; R³ is hydrogen atom or lower alkyl; X is methine; andY and Z are independently hydrogen atom, halogen, cyano, lower alkyl,halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, loweralkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² or-Q¹-Ar¹, or a salt or ester thereof, by reacting a compound of theformula (V):

 wherein y is hydrogen atom, halogen, cyano, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, loweralkylsulfonyl, lower alkylsulfonyloxy, —N(R^(1P))R^(2P),-Q^(1P)-Ar^(1P), or optionally protected hydroxy; Ar^(1P) is aryl orheteroaryl, any of which is optionally substituted by a substituentselected from the group consisting of halogen, nitro, lower alkyl,halo-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy,halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkanoyl,lower alkoxycarbonyl, lower alkanoylamino, -Q^(2P)-Ar^(2P), optionallyprotected oxo, optionally protected hydroxy, optionally protectedhydroxy-lower alkyl and optionally protected carboxyl; Ar^(2P) is arylor heteroaryl, any of which is optionally substituted by a substituentselected from the group consisting of halogen, cyano, lower alkyl,halo-lower alkyl, lower alkoxy, halo-lower alkoxy, di-lower alkylamino,lower alkanoyl, aryl, optionally protected hydroxy-lower alkyl,optionally protected hydroxy and optionally protected lower alkylamino;Q^(1P) and Q^(2P) are independently a single bond, oxygen atom,optionally protected carbonyl or—N(R³)—; R^(1P) and R^(2P) areindependently an amino-protecting group, an imino-protecting group,hydrogen atom or lower alkyl, or R^(1P) and R^(2P), taken together, formlower alkylene which may be interrupted by oxygen atom, sulfur atom oroptionally protected imino; and R³ has the same meaning as definedabove, or its salt, with a compound of the formula (VI):

 wherein L¹ is a leaving group; t, v and w are independently methine, uis nitrogen atom, said methine being optionally substituted by asubstituent selected from the group consisting of halogen, lower alkyl,halo-lower alkyl, lower alkoxy, halo-lower alkoxy, and optionallyprotected hydroxy; X has the same meaning as defined above; z ishydrogen atom, halogen, cyano, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl,lower alkylsulfonyloxy, —N(R^(1P))R^(2P), -Q^(1P)-Ar^(1P) or optionallyprotected hydroxy; and Ar^(1P), Q^(1P), R^(1P) and R^(2P) have each thesame meaning as defined above, or its salt to give a compound of theformula (VII):

 wherein t, u, v, w, X, y and z have each the same meaning as definedabove, and optionally removing the protecting group(s) therefrom.
 17. Aprocess for preparing a compound of the formula (I-3):

wherein Ar¹ is aryl or heteroaryl, any of which is optionallysubstituted by a substituent selected from the group consisting ofhalogen, nitro, oxo, hydroxy, lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy,halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² isaryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, cyano, loweralkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl; Q¹ and Q² are independently a single bond, oxygen atom,carbonyl or —N(R³)—; R¹ and R² are independently hydrogen atom or loweralkyl, or R¹ and R², taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or imino; T, V and W areindependently methine, U is nitrogen atom, said methine being optionallysubstituted by a substituent selected from the group consisting ofhalogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy andhalo-lower alkoxy; R³ is hydrogen atom or lower alkyl; X is methine; andY and Z are independently hydrogen atom, halogen, cyano, lower alkyl,halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, loweralkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² or-Q¹-Ar¹, or a salt or ester thereof, by subjecting a compound of theformula (VIII):

 wherein t, v and w are independently methine, u is nitrogen atom, saidmethine being optionally substituted by a substituent selected from thegroup consisting of halogen, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy and optionally protected hydroxy; y and z areindependently hydrogen atom, halogen, cyano, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, loweralkylsulfonyl, lower alkylsulfonyloxy, —N(R^(1P))R^(2P),-Q^(1P)-Ar^(1P), or optionally protected hydroxy; Ar^(1P) is aryl orheteroaryl, any of which is optionally substituted by a substituentselected from the group consisting of halogen, nitro, lower alkyl,halo-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy,halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkanoyl,lower alkoxycarbonyl, lower alkanoylamino, -Q^(2P)-Ar^(2P), optionallyprotected oxo, optionally protected hydroxy, optionally protectedhydroxy-lower alkyl and optionally protected carboxyl; Ar^(2P) is arylor heteroaryl, any of which is optionally substituted by a substituentselected from the group consisting of halogen, cyano, lower alkyl,halo-lower alkyl, lower alkoxy, halo-lower alkoxy, di-lower alkylamino,lower alkanoyl, aryl and optionally protected hydroxy-lower alkyl,optionally protected hydroxy and optionally protected lower alkylamino;Q^(1P) and Q^(2P) are independently a single bond, oxygen atom,optionally protected carbonyl or —N(R³)—; R^(1P) and R^(2P) areindependently an amino-protecting group, an imino-protecting group,hydrogen atom or lower alkyl, or R^(1P) and R^(2P), taken together, formlower alkylene which may be interrupted by oxygen atom, sulfur atom oroptionally protected imino; and X and R³ have each the same meaning asdefined above, and hydrazine to dehydrative ring closure to give acompound of the formula (IX):

 wherein t, u, v, w, X, y and z have each the same meaning as definedabove, and optionally removing the protective group(s) therefrom.
 18. Aprocess for preparing a compound of the formula (I-4):

wherein Ar¹ is aryl or heteroaryl, any of which is optionallysubstituted by a substituent selected from the group consisting ofhalogen, nitro, oxo, hydroxy, lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy,halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q² Ar²; Ar² isaryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, cyano, loweralkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl; Q¹ and Q² are independently a single bond, oxygen atom,carbonyl or —N(R³)—; R¹ and R² are independently hydrogen atom or loweralkyl, or R¹ and R², taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or imino; R³ is hydrogen atom orlower alkyl; T, V and W are independently methine, U is nitrogen atom,said methine being optionally substituted by a substituent selected fromthe group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy,lower alkoxy and halo-lower alkoxy; X is methine; and Y is hydrogenatom, halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, loweralkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl,lower alkylsulfonyloxy, —N(R¹)R² or -Q¹-Ar¹, or a salt or ester thereof,by reacting a compound of the formula (X):

 wherein y is hydrogen atom, halogen, cyano, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, loweralkylsulfonyl, lower alkylsulfonyloxy, —N(R^(1P))R^(2P), -Q^(1P)-Ar^(1P)or optionally protected hydroxy; Ar^(1P) is aryl or heteroaryl, any ofwhich is optionally substituted by a substituent selected from the groupconsisting of halogen, nitro, lower alkyl, halo-lower alkyl, cyclo-loweralkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio,lower alkylsulfonyl, lower alkanoyl, lower alkoxycarbonyl, loweralkanoylamino, -Q^(2P)-Ar^(2P), optionally protected oxo, optionallyprotected hydroxy, optionally protected hydroxy-lower alkyl andoptionally protected carboxyl; Ar^(2P) is aryl or heteroaryl, any ofwhich is optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy, di-lower alkylamino, lower alkanoyl, aryl,optionally protected hydroxy-lower alkyl, optionally protected hydroxyand optionally protected lower alkylamino; Q^(1P) and Q^(2P) areindependently a single bond, oxygen atom, optionally protected carbonylor —N(R³)—; R^(1P) and R^(2P) are independently an amino-protectinggroup, an imino-protecting group, hydrogen atom or lower alkyl, orR^(1P) and R^(2P), taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or optionally protected imino;and R³ has the same meaning as defined above, or its salt, with acompound of the formula (XI):

 wherein t, v and w are independently methine, u is nitrogen atom, saidmethine being optionally substituted by a substituent selected from thegroup consisting of halogen, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy and optionally protected hydroxy; and X hasthe same meaning as defined above, or its salt to give a compound of theformula (XII):

 wherein t, u, v, w, X and y have each the same meaning as definedabove, and optionally removing the protecting group(s) therefrom.
 19. Aprocess for preparing a compound of the formula (I-5):

wherein Az¹ is a group comprising a monocyclic azole having bondsattached respectively to the adjacent ring atoms, said monocyclic azolebeing optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy,lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, loweralkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹; Ar¹ is arylor heteroaryl, any of which is optionally substituted by a substituentselected from the group consisting of halogen, nitro, oxo, hydroxy,lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl,lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, loweralkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which isoptionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, loweralkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q¹ and Q² areindependently a single bond, oxygen atom, carbonyl or —N(R³)—; R¹ and R²are independently hydrogen atom or lower alkyl, or R¹ and R², takentogether, form lower alkylene which may be interrupted by oxygen atom,sulfur atom or imino; R³ is hydrogen atom or lower alkyl; and T, V and Ware independently methine, U is nitrogen atom, said methine beingoptionally substituted by a substituent selected from the groupconsisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, loweralkoxy and halo-lower alkoxy, or a salt or ester thereof, by reacting acompound of the formula (XIII):

 wherein Az^(1P) is a group comprising a monocyclic azole having bondsattached respectively to the adjacent ring atoms, said monocyclic azolebeing optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl,lower alkylsulfonyloxy, —N(R^(1P))R^(2P), -Q^(1P)-Ar^(1P), andoptionally protected hydroxy; Ar^(1P) is aryl or heteroaryl, any ofwhich is optionally substituted by a substituent selected from the groupconsisting of halogen, nitro, lower alkyl, halo-lower alkyl, cyclo-loweralkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio,lower alkylsulfonyl, lower alkanoyl, lower alkoxycarbonyl, loweralkanoylamino, -Q^(2P)-Ar^(2P), optionally protected oxo, optionallyprotected hydroxy, optionally protected hydroxy-lower alkyl andoptionally protected carboxyl; Ar^(2P) is aryl or heteroaryl, any ofwhich is optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy, di-lower alkylamino, lower alkanoyl, aryl,optionally protected hydroxy-lower alkyl, optionally protected hydroxyand optionally protected lower alkylamino; Q^(1P) and Q^(2P) areindependently a single bond, oxygen atom, optionally protected carbonylor —N(R³)—; R^(1P) and R^(2P) are independently an amino-protectinggroup, an imino-protecting group, hydrogen atom or lower alkyl, orR^(1P) and R^(2P), taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or optionally substituted imino;and R³ has the same meaning as defined above, or its salt, with acompound of the formula (XIV)

 wherein t, v and w are independently methine, u is nitrogen atom, saidmethine being optionally substituted by a substituent selected from thegroup consisting of halogen, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy and optionally protected hydroxy, or its saltor reactive derivative to give a compound of the formula (XV):

 wherein Az^(1P), t, u, v and w have each the same meaning as definedabove, followed by subjecting the compound (XV) to intramoleculardehydrative ring closure to give a compound of the formula (XVI):

 wherein Az^(1P), t, u, v and w have each the same meaning as definedabove, and optionally removing the protecting group(s) therefrom.
 20. Aprocess for preparing a compound of the formula (I-6):

wherein Ar¹ is aryl or heteroaryl, any of which is optionallysubstituted by a substituent selected from the group consisting ofhalogen, nitro, oxo, hydroxy, lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy,halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² isaryl or heteroaryl, any of which is optionally substituted by asubstituent selected from the group consisting of halogen, cyano, loweralkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy,halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl; Q¹ and Q² are independently a single bond, oxygen atom,carbonyl or —N(R³)—; R¹ and R² are independently hydrogen atom or loweralkyl, or R¹ and R², taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or imino; R³ is hydrogen atom orlower alkyl; T, V and W are independently methine, U is nitrogen atom,said methine being optionally substituted by a substituent selected fromthe group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy,lower alkoxy and halo-lower alkoxy; X is methine; and Y and Z areindependently hydrogen atom, halogen, cyano, lower alkyl, halo-loweralkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl,lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² or -Q¹-Ar¹, or asalt or ester thereof, by reacting a compound of the formula (II):

 wherein L¹ is a leaving group; y and z are independently hydrogen atom,halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, halo-loweralkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, loweralkylsulfonyloxy, —N(R^(1P))R^(2P), -Q^(1P)-Ar^(1P) or optionallyprotected hydroxy; Ar^(1P) is aryl or heteroaryl, any of which isoptionally substituted by a substituent selected from the groupconsisting of halogen, nitro, lower alkyl, halo-lower alkyl, cyclo-loweralkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio,lower alkylsulfonyl, lower alkanoyl, lower alkoxycarbonyl, loweralkanoylamino, -Q^(2P)-Ar^(2P) optionally protected oxo, optionallyprotected hydroxy, optionally protected hydroxy-lower alkyl andoptionally protected carboxyl; Ar^(2P) is aryl or heteroaryl, any ofwhich is optionally substituted by a substituent selected from the groupconsisting of halogen, cyano, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy, di-lower alkylamino, lower alkanoyl, aryl,optionally protected hydroxy-lower alkyl, optionally protected hydroxyand optionally protected lower alkylamino; Q^(1P) and Q^(2P) areindependently a single bond, oxygen atom, optionally protected carbonylor —N(R³)—; R^(1P) and R^(2P) are independently an amino-protectinggroup, an imino-protecting group, hydrogen atom or lower alkyl, orR^(1P) and R^(2P), taken together, form lower alkylene which may beinterrupted by oxygen atom, sulfur atom or optionally protected imino;and R³ has the same meaning as defined above, with a compound of theformula (XVII):

 wherein t, v and w are each independently methine, u is nitrogen atom,said methine being optionally substituted by a substituent selected fromthe group consisting of halogen, lower alkyl, halo-lower alkyl, loweralkoxy, halo-lower alkoxy and optionally protected hydroxy; and X hasthe same meaning as defined above, or its salt to give a compound of theformula (XVIII):

 wherein t, u, v, w, X, y and z have each the same meaning as definedabove, followed by subjecting the compound of the formula (XVIII) tointramolecular dehydrative ring closure to give a compound of theformula (XIX):

 wherein t, u, v, w, X, y and z have each the same meaning as definedabove, and optionally removing the protecting group(s) therefrom.
 21. Apharmaceutical composition comprising the compound of claim 1 togetherwith a pharmaceutically acceptable additive.